tier 3 toxicity value white paper - epa.gov · fda food and drug administration glp good laboratory...
TRANSCRIPT
U.S. ENVIRONMENTAL PROTECTION AGENCY OSWER 9285.7-86
Tier 3 Toxicity Value White Paper
Regional Tier 3 Toxicity Value Workgroup
OSWER Human Health Regional Risk Assessors Forum
5/16/2013
Disclaimer: This U.S. Environmental Protection Agency (EPA) document discusses the process of identifying and selecting Tier 3 toxicity values. This document is not a rule or regulation and it may not apply to a particular situation based upon the circumstances. This document does not change or substitute for any law, regulation, or any other legally binding requirement and is not legally enforceable. As indicated by the use of non-mandatory language such as “guidance,” “recommend,” “may,” “should,” and “can,” it identifies policies and provides recommendations and does not impose any legally binding requirements.
i
Table of Contents Acronyms and Abbreviations ...................................................................................................................... iv
1 Introduction .......................................................................................................................................... 1
1.1 Purpose ......................................................................................................................................... 1
1.1.1 Specific Objectives .................................................................................................................... 1
1.1.2 Scope ......................................................................................................................................... 1
1.2 Background ................................................................................................................................... 2
1.2.1 OSWER’s Toxicity Value Hierarchy....................................................................................... 2
1.2.1.1 Risk Assessment Guidance for Superfund (RAGS) Parts A and B ........................................ 2
1.2.1.2 2003 Directive Human Health Toxicity Values in Superfund Risk Assessments ................ 3
1.2.1.3 RAGS Part E and F ................................................................................................................. 3
1.2.2 Limitations of OSWER Guidance on Tier 3 Toxicity Value Selection .................................. 3
1.2.3 November 2009 Regional Risk Assessors Meeting .............................................................. 4
2 Tier 3 Toxicity Values ........................................................................................................................... 5
2.1 Sources .......................................................................................................................................... 5
2.1.1 Federal (Internal and External to EPA) ................................................................................ 5
2.1.2 State Toxicity Values ............................................................................................................ 6
2.1.3 International Community ..................................................................................................... 6
2.1.4 Databases for Developing Toxicity Values .......................................................................... 6
2.2 Similarities and Differences ......................................................................................................... 7
3 Existing Publications Relevant to Tier 3 Toxicity Value Evaluation, Selection, and Use .................... 8
3.1 Internal EPA Documents .............................................................................................................. 8
3.1.1 2003 Hierarchy (OSWER Directive 9285.7-53) ..................................................................... 8
3.1.2 Peer Review Handbook ........................................................................................................ 9
3.1.3 RAGS Part F ......................................................................................................................... 10
3.1.4 Risk Assessment Guidelines ............................................................................................... 10
3.1.5 Harmonized Test Guidelines .............................................................................................. 10
3.2 Environmental Council of the States ......................................................................................... 10
4 Current and Past Regional Practices in Identifying and Selecting Tier 3 Toxicity Values ................ 13
4.1 Regional Screening Levels Table (Selection Process) ................................................................ 13
4.2 Tier 3 Toxicity Value Consultations............................................................................................ 14
4.2.1 Chromium (VI) .................................................................................................................... 14
ii
4.2.2 Perfluorooctanic Acid and Perfluorooctane Sulfonate ..................................................... 15
4.2.3 Perchloroethylene .............................................................................................................. 16
4.2.4 Trichloroethylene ............................................................................................................... 16
5 Alternatives for Identifying, Evaluating, and Selecting, and Documenting Tier 3 Toxicity Values. 18
5.1 Toxicity Value Identification ...................................................................................................... 19
5.2 High vs. Low Priority ................................................................................................................... 19
5.3 Toxicity Value Evaluation (Criteria for Selecting a Tier 3 Toxicity Value) ................................ 21
5.3.1 Basic Requirements for Consideration as a Tier 3 Values ................................................. 22
5.3.2 Tier 3 Toxicity Value Critical Review .................................................................................. 22
5.3.2.1 Quality and Usability of Toxicity Testing Studies .............................................................. 22
5.3.2.2 Defining Adverse and Critical Effects ................................................................................. 23
5.3.2.3 Derivation of Noncancer and Cancer Toxicity Values ....................................................... 24
5.3.3 Tier 3 Toxicity Value Confidence ........................................................................................ 25
5.4 Options for Tier 3 Toxicity Value Consultations ........................................................................ 26
5.4.1 Action Development Process Workgroup ......................................................................... 27
5.4.2 Headquarters Consultation ................................................................................................ 27
5.4.3 Regional Workgroup .......................................................................................................... 29
5.4.3.1 Formal Regional Workgroup .............................................................................................. 30
5.4.3.2 Ad Hoc Regional Workgroups ............................................................................................ 30
5.4.4 Joint Headquarters/Regional Workgroup ......................................................................... 32
5.4.5 Individual Regions .............................................................................................................. 32
5.5 Documentation ........................................................................................................................... 33
5.5.1 Decision Documents and Distribution ............................................................................... 34
5.5.2 Repositories ........................................................................................................................ 34
5.5.2.1 PPRTV Assessments Electronic Library .............................................................................. 35
5.5.2.2 Superfund Health Risk Technical Support Center (STSC) .................................................. 35
5.5.2.3 RSL Table Website .............................................................................................................. 35
5.5.2.4 Tier 3 Toxicity Value Database ........................................................................................... 36
6 Recommended Option/Process and Path Forward .......................................................................... 37
6.1 Toxicity Value Identification ...................................................................................................... 37
6.2 Initial Evaluation and Chemical Prioritization ........................................................................... 39
6.3 Consulting Body .......................................................................................................................... 39
iii
6.3.1 Low-Priority Chemicals ....................................................................................................... 39
6.3.2 High-Priority Chemicals ...................................................................................................... 40
6.3.2.1 Tier 3 Toxicity Value Steering Committee ......................................................................... 40
6.3.2.2 Other Considerations ......................................................................................................... 41
6.4 Toxicity Value Evaluation ........................................................................................................... 41
6.5 Documentation ........................................................................................................................... 42
6.5.1 Decision Documents ............................................................................................................... 42
6.5.2 Repository ............................................................................................................................... 42
7 Summary ............................................................................................................................................. 43
References .................................................................................................................................................. 47
Figures
Figure 1. Tier 3 Toxicity Value Selection ................................................................................................... 18
Figure 2. Recommended Tier 3 Toxicity Value Selection Process............................................................. 38
Tables
Table 1. OPTIONS FOR TIER 3 CONSULTATIONS ........................................................................................ 46
Appendices
Appendix A: OSWER and ORD Organizational Charts
Appendix B: Tier 3 Toxicity Value Consultations
iv
Acronyms and Abbreviations
ADP Action Development Process
AEGL Acute Exposure Guideline Levels
ATSDR Agency for Toxic Substances and Disease Registry
BMDL Below minimal detection limit
Cal/EPA California Environmental Protection Agency
CERCLA Comprehensive Environmental Response, Compensation, and Recovery Act
DoD U.S. Department of Defense
ECOS Environment Council of the States
EPA U.S. Environmental Protection Agency
FDA Food and Drug Administration
GLP Good Laboratory Practice
HEAST Health Effects Assessment Summary Tables
HHMSSL Human Health Medium-Specific Screening Level
HQ Headquarters
IARC International Agency for Research on Cancer
IPCS International Programme on Chemical Safety
IRIS Integrated Risk Information System
ITER International Toxicity Estimates for Risk
IUR Inhalation unit risk
LOAEL Lowest observable adverse effect level
LOEL Lowest observed effect level
MCL Maximum contaminant level
mg/kg-day Milligrams per kilogram per day
v
MOA Mechanism of action
MOE Margin of exposure
MRL Minimal risk level
NCEA National Center for Environmental Health
NJDEP New Jersey Department of Environmental Protection
NOAEL No observed adverse effect level
NTP National Toxicology Program
NYSDOH New York State Department of Health
OECD Organization for Economic Co-operation and Development
OEHHA Office of Environmental Health Hazard Assessment
OEM Office of Emergency Management
OEPI Office of Policy, Economics & Innovation
OH2R2AF OSWER Human Health Regional Risk Assessors Forum
OMB Office of Management and Budget
OPM Office of Program Management
OPP Office of Pesticide Programs
ORCR Office of Resource Conservation and Recovery
ORD Office of Research and Development
OSRTI Office of Superfund Remediation & Technology Innovation
OSWER Office of Solid Waste and Emergency Response
OUST Office of Underground Storage Tanks
PARMS Policy Analysis & Regulatory Management Staff
PBPK Physiologically-based pharmacokinetic
PCE Perchloroethylene
PFOA Perfluorooctanic acid
vi
PFOS Perfluorooctane
PMCAO Program Management, Communications, and Analysis Office
ppm Parts per million
PPRTV Provisional Peer Reviewed Toxicity Values
RAGS Risk Assessment Guidance for Superfund
RBC Risk-based concentration
RCRA Resource Conservation and Recovery Act
RfC Reference concentration
RfD Reference dose
RIVM National Institute of Public Health and the Environment of the Netherlands
RME Reasonable maximum exposure
RP Responsible party
RSL Regional Screening Level
SAB Science Advisory Board
SPB Science Policy Branch
STSC Superfund Health Risk Technical Support Center
TCE Trichloroethylene
WHO World Health Organization
1
Tier 3 Toxicity Value White Paper 1
1 Introduction
1.1 Purpose
The purpose of this white paper is to articulate the issues pertaining to Tier 3 toxicity values and provide
recommendations on processes that will improve the transparency and consistency of identifying,
evaluating, selecting, and documenting Tier 3 toxicity values for use in the Superfund and Resource
Conservation and Recovery Act (RCRA) programs. This white paper will be used to assist regional risk
assessors in selecting Tier 3 toxicity values as well as provide the foundation for future regional and
national efforts to improve guidance and policy on Tier 3 toxicity values.
1.1.1 Specific Objectives
The specific objectives of this white paper are to:
• Inform the reader of the differences and similarities between Tier 3 toxicity values,
• Discuss existing criteria and guidance that are relevant to selecting the most scientifically
defensible Tier 3 toxicity value,
• Compare the available options for identifying, evaluating, selecting, and documenting Tier 3
toxicity values,
Provide specific examples of how Tier 3 toxicity values have been identified and selected by the
regions, and
• Recommend a process for selecting Tier 3 toxicity values.
1.1.2 Scope
This white paper is limited to Tier 3 toxicity values as defined in Office of Solid Waste and Emergency
Response (OSWER) Directive 9285.7-53 (2003 Toxicity Value Hierarchy) and provides recommendations
on processes for identifying, evaluating, selecting, documenting, and communicating Tier 3 toxicity
values for use in site-specific human health risk assessments.2 This white paper has been reviewed by
the regional risk assessors, and the recommendations are based on the consensus of the regional risk
assessors. While not guidance or policy itself, the white paper is also written with the intent to assist
1 Disclaimer: This U.S. Environmental Protection Agency (EPA) document discusses the process of identifying and
selecting Tier 3 toxicity values. This document is not a rule or regulation and it may not apply to a particular situation based upon the circumstances. This document does not change or substitute for any law, regulation, or any other legally binding requirement and is not legally enforceable. As indicated by the use of non-mandatory language such as “guidance,” “recommend,” “may,” “should,” and “can,” it identifies policies and provides recommendations and does not impose any legally binding requirements.
2 The derivation of new toxicity values falls outside of the scope of this white paper.
2
others (regional risk assessors, regional risk assessment workgroups, Regional Toxics Integration
Coordinators, and headquarters risk assessors) in developing formal or informal EPA regional and
national guidance or policy.
1.2 Background
Toxicity values (including reference doses [RfD], reference concentrations [RfC], cancer slope factors,
and inhalation unit risks) needed for use in human health risk assessment are generally derived by
reviewing available dose-response data in animals or humans, selecting a point of departure in the data
that is judged most suitable, and adjusting for associated uncertainties. Often, multiple data sets are
available, and there may be a variety of options for deriving the toxicity values. In addition, there are a
variety of options for fitting the data and selecting and applying uncertainty factors. For these reasons,
there can sometimes be a number of alternative toxicity factors available from different sources for a
specified chemical.
OSWER has developed a number of guidance documents which include recommendations for selecting
toxicity values. The early guidance established the IRIS database as the preferred source for selecting
toxicity values (EPA 1989, 1991, 1993). Subsequent guidance confirmed the preference for the use of
IRIS values and made suggestions for appropriate sources of toxicological information that could be used
for selecting or deriving toxicity factors in cases where no published IRIS value was available for a given
chemical. These developments have led to the concept of applying a more formal or prescribed
“hierarchy” for consulting data sources to select or derive toxicity values (EPA 2003, 2005, 2009). This
section describes the existing policies used by the Superfund Program for selecting toxicity values, and
when necessary, deriving appropriate values for site-specific risk assessment activities.
1.2.1 OSWER’s Toxicity Value Hierarchy
1.2.1.1 Risk Assessment Guidance for Superfund (RAGS) Parts A and B
The first guidance on the hierarchy for selecting toxicity factors was provided in Risk Assessment
Guidance for Superfund (RAGS) Part A (1989) and Part B (1991). These documents specify that the first
preference is for toxicity values that are presented in EPA’s Integrated Risk Information System (IRIS).
The 1993 OSWER Directive titled “Use of IRIS Values in Superfund Risk Assessment” reconfirmed that
IRIS values should be given the highest priority for application in Superfund risk assessments and that
alternative toxicological information should only be considered on a case-by-case basis
(http://www.epa.gov/oswer/riskassessment/pdf/irismemo.pdf). To this day, IRIS generally supersedes
all other sources of toxicity information and is considered the "gold-standard" in terms of toxicological
assessments. If no value was available in IRIS, the second preference was identified as the Health Effects
Assessment Summary Tables (HEAST). HEAST provided up-to-date toxicity values in a tabular format,
first quarterly and then annually for several years through 1997. Unlike IRIS, not all HEAST values went
through a formal peer or EPA review process, and interim values were also included in the tables.
3
If toxicity values were not available on IRIS or in HEAST, then RAGS recommended, in no specified order,
other sources such as EPA criteria documents (health advisory summaries), Agency for Toxic Substances
and Disease Registry (ATSDR) toxicological profiles, or provisional toxicity assessments prepared by the
National Center for Environmental Assessment (formerly the Environmental Criteria and Assessment
Office ).
1.2.1.2 2003 Directive Human Health Toxicity Values in Superfund Risk Assessments
In 2003, OSWER Directive 9285.7-53 revised Superfund’s hierarchy of human health toxicity values,
providing three tiers of toxicity values.3 There were two important reasons for updating the RAGS
toxicity hierarchy. First, additional sources of peer-reviewed values had become available, such as EPA's
Provisional Peer Reviewed Toxicity Values (PPRTVs). Second, HEAST, which had been identified in RAGS
as the second choice for toxicity information, had not been updated since 1997.
The revised hierarchy provided three tiers of toxicity values: IRIS as the first tier, PPRTVs as the second
tier, and "other toxicity values" as the third tier. Example sources of Tier 3 toxicity values included
California EPA (Cal/EPA) toxicity values, ATSDR Minimum Risk Levels (MRLs), and HEAST.
1.2.1.3 RAGS Part E and F
RAGS Part E (Dermal Guidance) and RAGS Part F (Inhalation Guidance) were the first supplemental
guidance documents to be published after the 2003 OSWER directive. Although RAGS Part E, which was
released in 2004, does not reference the 2003 OSWER directive or previous toxicity value hierarchies,
this guidance discusses a process for estimating dermal toxicity values by extrapolating from approved
oral toxicity values. In 2009, RAGS Part F cited the 2003 OSWER directive as the appropriate hierarchy
for selecting toxicity values. RAGS Part F notes that extrapolation of toxicity values from the oral to the
inhalation exposure route may not be appropriate in all cases.
1.2.2 Limitations of OSWER Guidance on Tier 3 Toxicity Value Selection
When no Tier 1 or Tier 2 toxicity value is available, but there are several Tier 3 values, it is necessary to
decide which Tier 3 value is most appropriate. The merit of these values may vary depending on the
scientific quality and rigor of the underlying toxicological studies and analysis and the extent of the peer
review. Development of some available values (such as ATSDR MRLs4 and Cal/EPA toxicity values),
includes extensive literature review, rigorous data analysis using up-to-date guidance and methods to
derive a toxicity value, and thorough peer review. Development of other toxicity values is not
3 As an OSWER Directive, the hierarchy is also used by the Office of Brownfields & Land Revitalization
(Brownfields), the Office of Emergency Management (OEM), the Office of Resource Conservation and Recovery
(ORCR), and the Office of Underground Storage Tanks (OUST).
4 ATSDR MRLs are limited to non-cancer effects only, but can include chronic, subchronic, and acute values.
4
necessarily based strictly on risk assessment practices, but may consider other factors. EPA Office of
Water maximum contaminant levels (MCLs), for example, may be based on technological limitations in
measurement or implementation.
The 2003 OSWER directive provides only limited guidance on selection of Tier 3 toxicity values,
recommending that priority should be given to studies that are the most current, transparent in terms
of their study or derivation methods, and that have been peer reviewed. Given the wide variety of
sources for Tier 3 toxicity values, further guidance is warranted to assist risk assessors to select the most
appropriate available Tier 3 value for use at Superfund and RCRA sites.
1.2.3 November 2009 Regional Risk Assessors Meeting
During a session of the November 2009 EPA Region Risk Assessors meeting, the regional risk assessors
presented and discussed the approaches, challenges, and limitations for identifying and selecting Tier 3
toxicity values. Specific issues covered during the session included, but were not limited to, existing
processes that regional risk assessors were using for identifying and selecting Tier 3 toxicity values,
differences between Tier 3 toxicity value sources (for example, derivation methods, transparency, and
use of uncertainty factors), and who is responsible for and what could be done to improve the Tier 3
toxicity value selection process. As a result of the presentations and ensuing discussions, the Regional
Tier 3 Toxicity Value Workgroup was formed, consisting of a small group of regional risk assessors. The
workgroup was given the broad task of developing processes for improving the selection of Tier 3
toxicity values. After the November meeting, the members of the workgroup met and charged
themselves with building upon OSWER’s toxicity value hierarchy by developing, evaluating, and
recommending a processes for identifying and selecting Tier 3 toxicity values. Given that the charge and
tasks were broad in scope, additional members and contacts were added to the workgroup, including
representatives from headquarters and the regions responsible for the Regional Screening Level Table.
Also, consistent with the workgroup’s charge and tasks specified during the November 2009 meeting,
the workgroup decided that these efforts would be documented in the form of a white paper.
5
2 Tier 3 Toxicity Values
Currently, there are a myriad of potential sources of ready-made Tier 3 toxicity values and additional
sources that provide the data necessary to derive a Tier 3 toxicity value. The purpose of this section is to
provide examples from each of these sources, since there are far too many to list. This section will also
introduce the similarities and differences between the sources of potential ready-made Tier 3 toxicity
values.
2.1 Sources
Tier 3 toxicity values and toxicity data can be derived from state, federal (U.S.), and international
sources. The following sections provide examples of some of the most commonly used state, federal
and international sources of Tier 3 toxicity values and toxicity data used by risk assessors.
2.1.1 Federal (Internal and External to EPA)
Both EPA and its individual program offices can be useful sources of Tier 3 toxicity values and data.
Before a chemical file is posted on the IRIS database in its final form, it must undergo a series of drafts,
internal and external peer reviews, and revisions. A major part of this process is development of the
draft toxicological review document for the individual chemical. This document details all of the
available human and animal toxicity data evaluated and the recommendation for a quantitative cancer
or noncancer toxicity value. Although the use of draft IRIS toxicity values as Tier 3 values is generally not
appropriate except as indicated in USEPA, 2003, the toxicity values and supporting data in the draft IRIS
toxicological reviews can be useful when evaluating a potential Tier 3 toxicity value from another
source. These draft documents are useful because the literature searches have been completed and
documented, the toxicity values derived using EPA-recommended methodologies, and to a greater or
lesser extent have undergone peer review. These draft toxicological reviews can be obtained from the
Region’s IRIS consensus reviewer and are posted on the web during the public review and comment
period.
Individual program offices often develop sources of toxicity values, which are not researched and peer
reviewed to the same extent as IRIS files, but are useful for specific chemicals and routes of exposure.
One example is the HEAST (http://epa-heast.ornl.gov/) developed for EPA’s Superfund and RCRA
hazardous waste programs. The Office of Pollution Prevention and Toxics Substances maintains the
Acute Exposure Guidelines Levels (AEGLs) database, which provides acceptable concentrations for once
in a lifetime, short-term exposures to airborne concentrations of acutely toxic, high priority chemicals
(http://www.epa.gov/oppt/aegl/index.htm). These acute values are based on the recommendations of
a federal advisory committee consisting of scientists from the public and private sectors. The Office of
Pesticide Programs and the National Center for Environmental Assessment in the Office of Research and
Development (ORD) are other potential sources of toxicity values.
6
Outside of EPA, perhaps the best known source of federal toxicity values is ATSDR. This agency develops
toxicological profiles for individual chemicals (available at
http://www.atsdr.cdc.gov/toxprofiles/index.asp), which are similar to the IRIS Toxicological Reviews. In
addition to a review of the available human and animal toxicity studies, the profiles recommend
quantitative values for risk management decision-making.
2.1.2 State Toxicity Values
A number of state environmental regulatory programs develop and maintain databases of quantitative
toxicity values. Perhaps the best known of these is the Cal/EPA toxicity values available on its Internet
website at http://www.oehha.ca.gov/risk/chemicalDB/index.asp. Examples of other state databases of
toxicity values include New Jersey Department of Environmental Protection
(http://www.state.nj.us/dep/dsr), and the Texas Department of Environmental Quality
(http://www.tceq.texas.gov/toxicology). States have also derived toxicity values for specific chemicals
and routes of exposure. For example, the New York State Department of Health (NYSDOH) developed
an air criteria document for trichloroethylene in 2006, which evaluated and derived noncancer and
cancer toxicity values (NYSDOH 2006).
2.1.3 International Community
Quantitative toxicity information can be found on the websites for many international regulatory
agencies. For example, Health Canada prepares screening assessments of priority chemicals under the
Canadian Environmental Protection Act of 1999
(http://www.chemicalsubstanceschimiques.gc.ca/plan/index-eng.php ). One database that provides
information from a number of international sources is the International Toxicity Estimates for Risk (ITER)
database, which can be found at http://iter.ctcnet.net/publicurl/pub_search_list.cfm. In addition to
EPA’s IRIS and the ATSDR databases, this site includes toxicity values from Health Canada, the
International Agency for Research on Cancer (IARC), the International Programme on Chemical Safety
(IPCS), the National Institute of Public Health and the Environment of the Netherlands (RIVM), as well as
peer-reviewed values by independent parties, such as Toxicological Excellence for Risk Assessment.
2.1.4 Databases for Developing Toxicity Values
In addition to state, federal, and international databases with cancer and noncancer toxicity values,
there are also a tremendous number of resources that can be researched to develop toxicity values for
specific chemicals.5 EPA has recently released ToxRefDB
(http://actor.epa.gov/toxrefdb/faces/Home.jsp). This database captures detailed study design, dosing,
and observed treatment-related effects on thousands of in vivo animal toxicity studies on hundreds of
chemicals. This database was developed by the National Center for Computational Toxicology in
5 The derivation of new toxicity values falls outside of the scope of this white paper. However, state, federal, and
international databases can be useful resources for evaluating existing Tier 3 toxicity values.
7
partnership with the Office of Pesticide Programs. Examples of other databases include the National
Library of Medicine Toxnet (http://toxnet.nlm.nih.gov/) and Micromedex
(http://www.micromedex.com/products/hcs/), and the National Toxicology Program (NTP;
http://ntp.niehs.nih.gov/). NTP provides toxicological information on over 500 chemicals through the
publication of general Technical Reports on chemicals and chemical mixtures and the Scientific Review
documents for chemicals and chemical agents which are listed in the Report on Carcinogens documents.
2.2 Similarities and Differences In How Toxicity Values Are Derived
As shown above, there are a large number of state, federal, and international resources for either
obtaining or developing Tier 3 toxicity values. When obtaining toxicity values and data from these
sources it is important to recognize that there are similarities and differences in how they develop
toxicity values. This is important when comparing methodologies from external agencies and
organizations to EPA’s methodologies, as well as when comparing competing toxicity values. Similarities
and differences may arise from the following elements:
The quality and usability of the animal and human studies used to derive the toxicity values
How adverse and critical effects are defined, and
The methodologies used to derive the cancer or noncancer toxicity value
The first two elements are common to most of the databases and toxicity values discussed above. The
methodologies used to calculate quantitative values are typically specific to the regulatory agency
involved. These elements or guiding principles, which will be further discussed in Section 5.3.2, will
serve as the basis for critical reviews of potential Tier 3 toxicity values.
In the case of competing toxicity values, differences between values may also be simply a result of the
age of the toxicity values. Newer values will likely have more studies underlying their derivation. In
addition, newer values may incorporate more current methods for evaluating dose/response
relationships, such as physiologically-based pharmacokinetic (PBPK) modeling.
Although not discussed further in this white paper, a basic understanding of how to evaluate and assess
the data usability of toxicity studies, identify the adverse and critical effect levels in a study, and
evaluate the regulatory-specific methodologies used to derive cancer and noncancer toxicity values is
useful for comparing, selecting, and developing chemical-specific toxicity values from multiple databases
(Ibid).
8
3 Existing Publications Relevant to Tier 3 Toxicity Value Evaluation, Selection, and Use
This section summarizes existing publications that are relevant to the evaluation, selection and use of
Tier 3 toxicity values. These publications include documents internal and external to EPA and include
policy directives, guidance documents, handbooks, guidelines, and issue papers. In addition to
summarizing these documents, the purpose of this section is to draw attention to elements of these
documents that are critical in the evaluation of potential Tier 3 toxicity values.
3.1 Internal EPA Documents
3.1.1 2003 Hierarchy (OSWER Directive 9285.7-53)
As discussed in Section 1.1.1.2, EPA's Superfund program revised its hierarchy of human health toxicity
values to incorporate EPA’s PPRTVs and address the aging HEAST toxicity values. Although the 2003
guidance established an overall hierarchy for selecting toxicity values, it did not attempt to rank Tier 3
sources. Instead, it provides examples of Tier 3 sources and general recommendations regarding the
prioritization of Tier 3 toxicity values. Specifically, in reference to Tier 3 toxicity values, the directive
states:
Priority should be given to sources that provide toxicity information based on similar
methods and procedures as those used for Tier I and Tier II, contain values which are
peer reviewed, are available to the public, and are transparent about the methods and
processes used to develop the values. Consultation with the Superfund Health Risk
Technical Support Center (STSC) or headquarters program office is recommended
regarding the use of the Tier 3 values for Superfund response decisions when the
contaminant appears to be a risk driver for the site. In general, draft toxicity
assessments are not appropriate for use until they have been through peer review, the
peer review comments have been addressed in a revised draft, and the revised draft is
publicly available.
Although the directive does not go into great detail on selection of Tier 3 toxicity values, it is clear that it
recommends that risk assessors select values that are derived using toxicological and risk assessment
methods that are:
(1) Consistent with the Agency’s methodologies;
(2) Transparent;
(3) Publicly available; and
(4) Have undergone peer review.
In addition, the directive recommends the involvement of ORD (Superfund Technical Support Center
[STSC]) and headquarters and cautions against the use of draft toxicity values to ensure the scientific
defensibility of Tier 3 toxicity values, especially risk-driving chemicals.
9
3.1.2 Peer Review Handbook
As indicated in the 2003 hierarchy memorandum and other publications specific to toxicity value
selection and use (see for example, EPA 2009; ECOS 2007), peer review is one of several critical
elements in selecting or giving preference to one toxicity value over another. Although not necessarily
specific to toxicity value selection, EPA’s Peer Review Handbook (EPA 2006) provides important
information that is applicable to the evaluation and selection of Tier 3 toxicity values. The 3rd edition of
the peer review handbook defines peer review as the following:
Peer review is a documented critical review of a specific Agency scientific and/or
technical work product. Peer review is conducted by qualified individuals (or
organizations) who are independent of those who performed the work, and who are
collectively equivalent in technical expertise (i.e., peers) to those who performed the
original work. Peer review is conducted to ensure that activities are technically
supportable, competently performed, properly documented, and consistent with
established quality criteria. Peer review is an in-depth assessment of the assumptions,
calculations, extrapolations, alternate interpretations, methodology, acceptance criteria,
and conclusions pertaining to the specific major scientific and/or technical work product
and of the documentation that supports them. Peer review may provide an evaluation of
a subject where quantitative methods of analysis or measures of success are unavailable
or undefined such as research and development. Peer review is usually characterized by
a one-time interaction or a limited number of interactions by independent peer
reviewers. Peer review is encouraged during the early stages of the project or methods
selection, and/or as part of the culmination of the work product, as appropriate.
Regardless of the timing of peer review, the goal is ensuring that the final product is
technically sound. (USEPA, 2006a)
The importance of peer-review is re-affirmed in EPA’s 2006 peer review policy, which states:
Peer review of all scientific and technical information that is intended to inform or
support Agency decisions is encouraged and expected. Influential scientific information,
including highly influential scientific assessments, should be peer reviewed in accordance
with the Agency’s Peer Review Handbook. All Agency managers are accountable for
ensuring that Agency policy and guidance are appropriately applied in determining if
their work products are influential or highly influential, and for deciding the nature,
scope, and timing of their peer review. For highly influential scientific assessments,
external peer review is the expected procedure. For influential scientific information
intended to support important decisions, or for work products that have special
10
importance in their own right, external peer review is the approach of choice (USEPA,
2006b).6
3.1.3 RAGS Part F
RAGS Part F also provides guidance on evaluation and selection of a Tier 3 toxicity value. In reference to
EPA’s toxicity value hierarchy, RAGS Part F states, “Priority in Tier 3 should be given to sources that are
the most current and those that are peer reviewed. Consultation with the Superfund Headquarters
office is recommended regarding the use of Tier 3 values for Superfund response decisions when the
contaminant appears to be a risk driver for the site.” In addition, this guidance provides a list of
circumstances when route-to-route extrapolations from oral toxicity values might not be appropriate.
This information could be useful in evaluating Tier 3 toxicity values that are based on route-to-route
extrapolations.
3.1.4 Risk Assessment Guidelines
Multiple risk assessment guidelines have been published by EPA ranging from the Guidelines for
Mutagenicity Assessment (1986) to the 2005 Guidelines for Carcinogen Risk Assessment. These
guidelines , as well as other guidance documents pertaining to development of toxicity values (1994
Methods for Derivation of Inhalation Reference Concentrations [RfCs] and Application of Inhalation
Dosimetry) provide specific guidance (including criteria to be met) on how the Agency derives toxicity
values. These documents have and will continue to serve as the benchmark for evaluating toxicity
values external to EPA.
3.1.5 Harmonized Test Guidelines
EPA’s harmonized test guidelines (http://www.epa.gov/ocspp/pubs/frs/home/guidelin.htm) are
documents that specify methods for use in testing pesticides and toxic substances and developing test
data for submittal to the Agency. The guidelines typically specify the species to be tested, routes of
administration, doses to be administered, and duration of study and endpoints to be assessed. These
guidelines serve as the “gold standard” for performing toxicity testing and studies and, similar to the risk
assessment guidelines discussed in Section 3.1.4, serve as a benchmark for evaluating the adequacy of a
toxicity value’s underlying study or studies.
3.2 Environmental Council of the States
6 Influential scientific and highly influential scientific assessments involve precedential, novel, “cutting edge,” or
controversial issues, or the Agency has a legal or statutory obligation to conduct a peer review. Highly influential
scientific assessments have a higher degree of influence, substance, interagency interest, and economic impact
(EPA 2006a).
11
In April 2007, the Environmental Council of the States-U.S. Department of Defense Sustainability Work
Group (ECOS-DoD Sustainability Work Group) released the issue paper (ECOS paper) titled
“Identification and Selection of Toxicity Values/Criteria for Comprehensive Environmental Response,
Compensation, and Recovery Act (CERCLA) and Hazardous Waste Site Risk Assessments in the Absence
of IRIS Values.” The ECOS paper, which was written in collaboration with EPA, Cal/EPA, and Department
of Defense (DoD) scientists and risk assessors, is intended to provide guidance and a suggested
framework for identifying and selecting toxicity values in the absence of IRIS values. The ECOS paper
provides this guidance and framework in the form of seven preferences for identifying and ranking
toxicity values. These preferences are provided below.
(1) There should be a preference for transparent assessments (in which toxicity values are
derived), that clearly identify the information used and how it was used.
(2) There should be a preference for assessments which have been externally and independently
peer reviewed, where reviewers and affiliations are identified. Other things being equal, there
should also be a preference for assessments with more extensive peer review. Panel peer
reviews are considered preferable to letter peer reviews.
(3) There should be a preference for assessments that were completed with a previously
established and publicly available methodology. Methodologies that themselves were
externally peer reviewed are preferred over those that were not externally peer reviewed.
(4) While there should be a preference for assessments using established methodologies to derive
toxicity values, these methodologies should also be informed by the current best scientific
information and practices. New assessment methodologies should provide reproducible
results and meet quality assurance and quality control requirements.
(5) There should be a preference for assessments that consider the quality of studies used,
including the statistical power or lack thereof to detect effects; that corroborate data amongst
pertinent studies; and that make best use of all available science.
(6) There should be a preference for assessments and values which are publicly available or
accessible. There may be a further preference for toxicity assessments that invited and
considered public comment (as well as, but not in lieu of, external peer review).
(7) Other things being equal, there should be a preference for toxicity values that are consistent
with the duration of human exposure being assessed. For example, an externally peer
reviewed subchronic reference dose (RfD) should be preferred to an externally peer reviewed
chronic RfD when assessing an exposure of 2 years for non-cancer toxicity. (ECOS 2007)
12
In conjunction with these seven preferences, the ECOS paper provides additional recommendations
relevant to the selection of toxicity values. They include the overarching principle that risk assessors
should continue to identify the most scientifically defensible toxicity value and that the selecting
individuals have an understanding of the available sources of toxicity data and their strengths and
weaknesses so that the most appropriate toxicity value is selected. Furthermore, although the seven
preferences are generally intended for existing toxicity values, the ECOS paper specifically states that
the preferences may be “used if an agency or party would like to propose an alternative to a toxicity
value” (ECOS 2007).
13
4 Current and Past Regional Practices in Identifying and Selecting Tier 3 Toxicity Values
The purpose of this section is to summarize past and current practices used by regional and
headquarters risks assessors to evaluate and select Tier 3 toxicity values. Specifically, this section
discusses the evaluation and selection processes employed by the regional risk assessors to derive the
regional screening levels. Also, this section provides detailed summaries of Tier 3 toxicity value
consultations provided by regional and headquarters risk assessors.
4.1 Regional Screening Levels Table (Selection Process)
Risk-based screening levels for soil, air, and water have been in existence for nearly 20 years in EPA's
Superfund Program. Similar to human health risk assessments, screening levels are derived using
chemical-specific toxicity values combined with standard exposure factors that reflect Superfund's
concept of a reasonable maximum exposure (RME). They have traditionally represented the point of
departure of an excess lifetime cancer risk level of 1E-06 or a Hazard Quotient of 1 for noncancer
effects.
In the past, risk-based screening levels were compiled in individual regional tables such as the Risk-
Based Concentrations (RBC) table published by Region 3, the Human Health Medium-Specific Screening
Levels (HHMSSL) table published by Region 6, and the Preliminary Remediation Goals (PRG) table
published by Region 9. In general, if a substance had been assigned an EPA toxicity value, it was listed in
the individual regional screening tables. In the case where a substance had more than one possible
toxicity value, a toxicity hierarchy first described in RAGS Part A was applied. In some cases, each Region
developed its own unique values (e.g., Region 3 RBCs for Fish Consumption).
One consequence of the 2003 toxicity values hierarchy memorandum (Human Health Toxicity Values in
Superfund Risk Assessments, OSWER Directive 9285.7-53, December 5, 2003) was that the risk screening
tables needed to be revised to reflect the new Agency preference for toxicity values. The guidance was
clear with respect to the first two tiers in the hierarchy, and these tiers were used as "defaults" in the
regional tables. However, it was less clear what was to be used as a Tier 3 source when there are
competing sources. This lack of clarity could have led to inconsistencies in the regional screening tables
if, for example, Region 3 used a different Tier 3 source than Region 9 or Region 6.
The regional offices that created screening tables have had a long history of communication and
coordination to reduce (if not avoid) inconsistencies among the individual tables. Nonetheless,
inconsistencies still existed. An important milestone was reached in 2008, when the various regional
tables were harmonized into a single majority-consensus table known as the Regional Screening Levels
(RSL) table. This table updated and superseded previous regional tables. Individual Regions are still able
to develop independent (or non-consensus) screening values, however, they are not published as part of
the RSL table. Individual Regions may also choose Tier 3 values different from the RSL table. It is not the
responsibility of the RSL table workgroup to choose for, or dictate to the Regions. The RSL table
workgroup merely makes recommendations. Representatives from all EPA regions and HQ are
14
encouraged to participate in the RSL table workgroup so that their valuable input is incorporated in the
periodic updates and revisions to the screening table.
Establishing which toxicity values to use when there are no applicable Tier 1 or Tier 2 values is a
challenge because the 2003 guidance did not provide a ranking or hierarchy for Tier 3 sources The RSL
workgroup has proposed and implemented a tentative ranking of Tier 3 sources to include in the
screening table. The RSL workgroup readily acknowledges that other toxicity values (e.g., State values)
could be used to develop the screening values. It is NOT the mission or goal of the RSL workgroup to
independently develop Tier 3 toxicity reference values in the absence of other sources, nor is it a
practice of the workgroup to review values from all potential sources.
At present, the Tier 3 toxicity values from the following sources in the order in which they are presented
below are used as the defaults in the RSL tables.
(1) The ATSDR Minimal Risk Levels (MRLs)
(2) Cal/EPA, Office of Environmental Health Hazard Assessment (OEHHA), toxicity values
(3) PPRTV Appendix "Screening Toxicity Values"
(4) HEAST
These sources are credible (rely on best available science, have undergone a high degree of scrutiny and
peer review, are often considered by other Agencies).
An RSL calculator is also provided, which allows the user to use a different toxicity value or exposure
assumptions other than the defaults. The RSL group anticipates that RSL’s provisional hierarchy may
change in the future to reflect recommendations in this white paper.
4.2 Tier 3 Toxicity Value Consultations
When there is no established Tier 3 value for high-priority chemicals that are likely to be risk drivers at a
site, the regions have often performed their own evaluations of the science and/or sought headquarters
guidance. With respect to headquarters consultations, key offices that have been involved include, but
are not necessarily limited to, OSWER/OSRTI/SPB, OSWER/OEM, OSWER/OPM/PARMS,
OSWER/ORCR/PMCAO, and ORD/NCEA. Below are several examples of how Tier 3 values have been
evaluated and selected in the past at the regional and headquarters level.
4.2.1 Chromium (VI)
The 1998 IRIS file for chromium (VI) identified it as an inhalation carcinogen and provided an inhalation
unit risk (IUR), but oral carcinogenicity could not be determined because no data were located in the
available literature that suggested it was carcinogenic by the oral route of exposure (EPA 1998).
However, several years later, a study by the National Toxicology Program (NTP) stated that oral
exposure to chromium (VI) “provided clear evidence of carcinogenic activity in male and female rats and
15
mice based on the presence of benign and malignant tumors in rat oral mucosa and mouse small
intestine” (NTP 2008) and suggested that the compound may be carcinogenic by mutagenic mode of
action. In response to this study, some states (New Jersey and California) began the process of revising
their water and soil standards based on the NTP study. EPA’s Office of Pesticide Programs (OPP) also
developed an oral slope factor and published a journal article on the chemical’s mutagenic mode of
action to support its risk assessment of chromated copper arsenate (McCarroll et al. 2010). In
November 2008, the IRIS program began the reassessment of chromium VI for the oral route of
exposure.
Region 2 appealed to headquarters in 2009 for guidance while working on a removal site because the
state of the science had evolved faster than IRIS could be updated and several potential Tier 3 toxicity
values were available. Specifically, Region 2 requested consultation on the use of New Jersey’s oral
slope factor (NJDEP 2009). In this request, Region 2 noted that although several potential Tier 3 sources
are available, only New Jersey’s oral slope factor met all the criteria in the 2003 hierarchy directive. The
request was submitted to the Senior Science Advisor for OSWER on August 17, 2009, who consulted
with representatives of OSRTI and OEM and concurred with this conclusion in an e-mail on September
28, 2009 (see Appendix B).
4.2.2 Perfluorooctanic Acid and Perfluorooctane Sulfonate
Perfluorooctanic acid (PFOA) and perfluorooctane sulfonate (PFOS) are emerging contaminants that
have been found at sites in Region 4 and other regions. Because no toxicity values for these compounds
are currently available in the IRIS or PPRTV databases, Region 4 requested that OSWER recommend
what toxicity values would be appropriate to use. In response, OSRTI and OEM consulted scientists from
EPA’s Office of Water, Office of Pollution and Toxic Substances, and the Office of Research and
Development regarding the use of the Office of Water’s 2009 Provisional Health Advisories for PFOA and
PFOS.
In an October 28, 2009, memorandum (see Appendix B), OSRTI and OEM recommended use of the
provisional drinking water advisories for PFOA and PFOS and interim subchronic RfDs based on the
advisory levels. Because the drinking water advisories address only water, OSWER’s consultation
included derivation of subchronic RfDs so that they could be used to derive removal action levels or
screening levels for water and other media. The memorandum also outlines the ways the Provisional
Health Advisories meet the criteria for a Tier 3 toxicity value as established in the hierarchy directive.
Specifically, the consultation memorandum notes that the provisional advisories underwent internal and
external review and draws attention to similarities between the Office of Water’s methodology for
deriving provisional advisory levels (and the subsequent subchronic RfDs) and IRIS assessments (deriving
toxicity values using Benchmark Dose Level (BMDL), no observed adverse effects level [NOAEL], or
lowest observed adverse effects level [LOAEL]).
16
4.2.3 Perchloroethylene
At about the time the 2003 toxicity value hierarchy was being finalized and released to the regional risk
assessors, regions sent inquiries to OSWER regarding the use of Cal/EPA’s cancer toxicity values for
perchloroethyelene (PCE). Found at nearly half of all Superfund sites (ATSDR 1997), including numerous
vapor intrusion sites, having toxicity values for this chemical was key to moving risk assessments and
remedy decisions forward. Moving these activities forward was of special concern given that health
organizations, such as IARC, had classified PCE as a probable human carcinogen (IARC 1995).7
In response, the Deputy Director of the Office of Emergency and Remedial Response (currently OSRTI),
in consultation with the STSC, sent a letter to Region 10 on June 12, 2003, supporting the use of
Cal/EPA’s IUR and oral slope factor (see Appendix B), noting that there are similarities between how
Cal/EPA and the IRIS program develop toxicity values and that Cal/EPA’s presentation on how the
toxicity values were developed is full, complete, and transparent. In regards to transparency and the
use of the values in Superfund Program decision-making, the letter recommended that the appropriate
documentation or link to the Cal/EPA website be provided. In addition, the letter included an excerpt
from a Cal/EPA technical support document pertaining to PCE’s inhalation unit risk value.
4.2.4 Trichloroethylene
Trichloroethylene (TCE), which is found at more than 1,500 sites, has a long and complicated history at
EPA, especially within the IRIS and Superfund Programs. The IRIS cancer assessment and cancer toxicity
values for TCE, which were released in 1987, were withdrawn in 1989.8 Between 1989 and 2001,
regions generally relied on the withdrawn values. In 2001, NCEA completed a preliminary draft
assessment of the health risks posed by TCE. The new toxicity values, especially the cancer toxicity
values, dramatically increased the calculated risks at the same exposure. Although these values were
not loaded into the IRIS database, some regions continued to use them since they were briefly endorsed
by STSC. After review by EPA’s Science Advisory Board (SAB) in 2002, STSC no longer supported the use
of the 2001 draft values. However, several regions continued to use the 2001 draft toxicity values. After
the 2003 toxicity hierarchy memorandum was released, some regions began using the Cal/EPA toxicity
values for TCE or a combination of Cal/EPA toxicity values and the 2001 draft toxicity values, while
others continued to use only the 2001 draft toxicity values. The Region 9 PRG, Region 3 RBC, and Region
6 MSSLs used the 2001 draft noncancer and cancer toxicity values up until approximately the time the
tables were consolidated into the RSLs in 2008. In 2008, the RSL tables began using the Cal/EPA cancer
toxicity values.
7 Prior to PCE’s final Toxicological Review, which was posted on IRIS on February 10, 2012, IRIS only provided an
RfD.
8 TCE’s final Toxicological Review was posted on IRIS on September 28, 2011.
17
In 2006, the NYSDOH released the Trichloroethene Air Criteria Document. That document, which
underwent peer review, provided a noncancer inhalation toxicity value comparable to an EPA RfC.
Because the NYSDOH toxicity value was final, had undergone peer-review, and its derivation was
transparent, some regions began considering use of the value to assess noncancer health risks. Its use
in risk assessments was significant, especially with respect to the vapor intrusion into indoor air
pathway, because the NYSDOH value results in residential indoor air noncancer screening levels
corresponding to a cancer risk of approximately 1E-05. In comparison, Cal/EPA provides a noncancer
chronic REL that is 60 times greater than the NYSDOH value.
In 2008, Region 10 advised its states about Region 10’s evaluation of TCE and provided two options for
evaluating cancer risk: (1) use the geometric midpoint of the slope factor range from the 2001 NCEA
assessment, or (2) use the Cal/EPA oral slope factor and inhalation unit risk, but adjust them upward by
a factor of 10. When noncancer health hazards are evaluated, Region 10 recommended using the
NYSDOH criterion.
In January 2009, OSWER released guidance on the recommended cancer and noncancer toxicity values
(Cal/EPA cancer toxicity values and the NYSDOH noncancer inhalation toxicity value) (see Appendix B).
The memorandum provided an extensive summary and evaluation of the available toxicity values from
Cal/EPA, NYSDOH, and the Indiana Department of Environmental Management. It included a discussion
on the toxicity values’ underlying studies and methods used to derive the toxicity values and a detailed
comparison of the competing noncancer inhalation toxicity values. However, the memo was withdrawn
by OSWER in April 2009 to further evaluate the recommendations regarding the noncancer toxicity
values for use in inhalation risk assessments (see Appendix B).
In April 2009, Region 7 provided guidance to the regional RCRA and Superfund programs on TCE toxicity
values (see Appendix B). Specifically, the regional risk assessors recommended the use of the Cal/EPA
cancer toxicity values and the NYSDOH non-cancer inhalation toxicity value, citing that they met the
requirements of Tier 3 toxicity values (for example, had been peer-reviewed). With regards to the
competing inhalation toxicity values, Region 7 provided rationale for selecting the NYSDOH value over
the Cal/EPA REL.
During the spring 2011 RSL table update, the RSL workgroup provided a noncancer RfC for TCE based on
the value derived by the NYSDOH (NYSDOH 2006).
18
5 Alternatives for Identifying, Evaluating, and Selecting, and Documenting Tier 3 Toxicity Values
As discussed in Section 1, the overall goal of the Regional Tier 3 Toxicity Value Workgroup is to establish
a process that enhances the transparency and consistency of Tier 3 toxicity value identification,
evaluation, selection, documentation, and communication. The steps in the overall process for selecting
Tier 3 toxicity value are shown in Figure 1 below and described in the following sections. For this white
paper, communication refers to the flow of information and overall coordination leading to selection
and documentation of a Tier 3 toxicity value. Therefore, communication is part of the other steps and is
not shown as a separate step. In addition, the priority of a chemical (regional or national interest) may
play a significant role in determining the overall selection process and is therefore listed as a step in the
selection process.
Figure 1. Tier 3 Toxicity Value Selection
Regions, HQ, or Workgroup
Toxicity value meets Tier 3
criteria?
Decision Making Body
Tier 3 Toxicity Value Criteria
Tier 3 Toxicity Value is Evaluated
Potential Tier 3 Toxicity Value is Identified
Technical support
document(s)
Document and file
Value not recommended
Yes No
Chemical Priority is Identified
19
5.1 Toxicity Value Identification
The regional risk assessors and RSL workgroup9, through their routine work (site risk assessments and
table updates), regularly encounter chemicals without Tier 1 and Tier 2 toxicity values. Thus, the
identification of potential Tier 3 toxicity values has been largely their responsibility. This approach
continues to be an option, however, this white paper also presents other potential avenues for
identifying Tier 3 toxicity values. As an alternative to the regional risk assessors and RSL workgroup, a
formal toxicity workgroup could be charged with identifying Tier 3 toxicity values, as well as other
responsibilities (see Section 5.4.3.1). Although this responsibility is similar to the RSL workgroup, which
looks at a broad range of chemicals, it is envisioned that the formal workgroup would look for potential
Tier 3 toxicity values beyond the sources consulted by the RSL workgroup (for example, international
sources). Furthermore, the workgroup’s identification of potential Tier 3 toxicity could outpace the RSL
workgroup because the former’s sole focus would be to identify, evaluate, select, document, and
communicate Tier 3 toxicity values.
If the responsibility for identifying potential Tier 3 toxicity values were assigned to a formal workgroup,
several issues would need to be considered. First, the establishment of a new workgroup (assuming
responsibilities are not subsumed within an existing workgroup) would require time and resources. In
addition, it is uncertain whether the workload (new values being made available) would be sufficient to
keep the group active. Furthermore, regional risk assessors and others will likely continue to search for
Tier 3 toxicity values in their routine work (conducting risk assessments), leading to a duplication of
effort. Thus, the value added of a formal workgroup is uncertain and would likely require the group to
have multiple responsibilities to maintain member interest.
5.2 High vs. Low Priority
As a result of resource constraints, time, and other limitations and difficulties (such as potential
controversy surrounding some chemicals), it is likely that no one alternative will be suitable as the sole
means of evaluating and selecting all Tier 3 toxicity values. Thus, the priority of the chemical will likely
dictate the entity that will evaluate and select a Tier 3 toxicity value. For instance, the examples
provided in Section 4 clearly indicate that high-priority chemicals are elevated to headquarters.
The process for elevating Tier 3 toxicity values to headquarters and other entities (such as the RSL
workgroup) has been rather informal in the past. If a more formalized and structured system of selecting
Tier 3 toxicity values is implemented, a formal process for determining a chemical’s priority may be
needed, including criteria for distinguishing between those chemicals of low, medium, and high priority.
This determination can be subjective and vary among the regions. Factors to consider in evaluating
priority are described below. Of course, decision-making in regard to these criteria, especially a
9 During the development of site-specific risk assessments, potentially responsible parties may identify Tier 3
toxicity values.
20
chemical’s prevalence, may require coordination among the regions and headquarters, and the formal
process may reinforce this requirement. Continued coordination and communication among potential
decision-makers is also important so that elevation of a Tier 3 value to a headquarters or regional
workgroup is efficient (chemicals are not elevated and then demoted).10
Below are a set of prioritization criteria that could be used to assist risk assessors, risk managers and
others in assigning priority to a contaminant. Answering one of the questions below in the affirmative
may not be sufficient to designate a contaminant as high priority. However, a preponderance of
evidence should be adequate to support a high-priority designation. A contaminant with a high-priority
designation would likely require a Tier 3 consultation by headquarters or a regional workgroup to ensure
consistency across the Regions. Tier 3 contaminants that are not expected to drive health risks or
remediation at a site, may be associated with mild health effects, are not encountered across multiple
regions, or are not being considered for national rule making may be considered low priority. In this
case, the decision to develop a Tier 3 toxicity value may be best left up to the individual region.11
Prioritization Criteria
Does the contaminant have the potential to drive risks estimates and remediation at a site?
Answering this question requires a minimum of toxicity information, such as a single subchronic
or developmental study administered by the route of exposure expected to occur at the site. This
information may be available from the database sources described in Section 2.1 or via an open
literature search. If the answer to the question is yes, then the contaminant may be a candidate
for a high-priority designation.
10
Because regional risk assessors that submit potential Tier 3 toxicity values may have significant knowledge of the
chemical, they may remain involved in the evaluation and selection process.
11 In cases where the priority of a chemical falls somewhere in between high and low, best professional judgment
should be used in deciding whether that chemical should be evaluated by headquarters or a regional workgroup
(chemical evaluated as high priority) versus individual region (chemical evaluated as low priority). In cases of
uncertainty, it is recommended a request be sent to the “Tier 3 Toxicity Value Steering Committee” (further
discussed in Section 6.2), which would decide the priority designation and ultimately the proper action to be taken
on a chemical-specific basis.
21
Based on the available toxicity information and the concentration measured at the site, would
the estimated human health effects be expected to be severe (irreversible damage affecting the
function or viability of a receptor or target organ), moderate, or mild (transient, reversible
effects)?
Similar to the first question, answering this question requires a minimum of toxicity information.
If the information suggests that the health effects to an individual would be severe or moderate,
then the contaminant may be considered a high priority.
Is the contaminant associated with a source or industry that is common across the region or
multiple regions?
The more prevalent a contaminant, especially across multiple regions, the more likely it is to
receive a high-priority designation.
Based on the chemical and physical properties of the contaminant, how likely is it that the
remediation techniques used for the known risk drivers at the site would also remediate the
contaminant in question?
This question is not necessarily toxicological, but instead is a risk management question. If the
remediation techniques being used at a site for the known risk drivers will also be successful in
cleaning up the contaminant in question (based on what is known about the chemical and
physical properties), it may not be efficient or necessary to delay a project while a Tier 3 toxicity
value is being evaluated.
Is the contaminant under consideration for rulemaking nationally?
If EPA is considering the contaminant for rulemaking purposes, it should automatically be
considered as a high-priority candidate. The best approach would be to ensure a consistent
toxicity value across all regions and program offices because of the public visibility of the
contaminant.
5.3 Toxicity Value Evaluation (Criteria for Selecting a Tier 3 Toxicity Value)
Per EPA risk assessment guidance and other relevant risk assessment publications, the ultimate goal of
selecting a toxicity value for use in risk assessment is to select the most current and scientifically
defensible value. With regard to the selection of Tier 3 toxicity values, this value is selected by applying
a combination of the general guidance principles discussed in Section 2.2 and the recommendations and
preferences discussed in EPA and non-EPA risk assessment guidance (see Section 3). The following
sections outline a proposed process that could be used to evaluate and select Tier 3 toxicity values.
22
5.3.1 Basic Requirements for Consideration as a Tier 3 Values
After a potential Tier 3 toxicity value has been identified, the first step is to determine whether that
value meets the basic requirements of a Tier 3 value. As discussed in OSWER’s 2003 Toxicity Value
Hierarchy, three key factors for a toxicity value to be considered in the selection of a scientifically
defensible Tier 3 value are that the value is peer-reviewed, publically available, and that the source is
transparent about the methods and procedures used to develop the value. These same factors are also
discussed in several of the seven preferences provided in the ECOS paper and echoed in other EPA
guidance (such as RAGS Part F). Despite the requirements implied in the aforementioned documents,
the level of peer-review is not specified. Thus, per EPA’s peer review policy, decision-makers (the entity
evaluating a potential Tier 3 toxicity value) have to consider whether the level of peer review matches
the significance of the chemical. Availability and transparency are more straightforward. However,
decision-makers have to determine, for example, whether an Internet posting of a summary file of a
toxicological assessment (instead of the entire toxicological file) meets the availability and transparency
criteria unless an internet link to the entire file is provided.
It is also important to evaluate the quality and usability of the underlying data supporting the potential
Tier 3 value. Although a precise level of data quality and usability has not been defined, some toxicity
values may not be of suitable quality or usability even though they have been peer-reviewed and are
publically available. For example, some toxicity values may be based on route-to-route extrapolations of
peer-reviewed values. Therefore, this step may focus on major deficiencies that would preclude use of a
potential Tier 3 toxicity value. When competing Tier 3 values are available, this step may also indicate
the preferred value.
5.3.2 Tier 3 Toxicity Value Critical Review
Section 2.2 introduced the general guiding principles for evaluating the quality and usability of Tier 3
toxicity values. Specifically:
(1) The quality and usability of the animal and human studies used to derive the toxicity values,
(2) How adverse and critical effects are defined, and
(3) The methodologies used to derive the cancer or noncancer toxicity value.
This white paper proposes the use of the guiding principles to conduct a more critical evaluation of the
potential Tier 3 toxicity value.
5.3.2.1 Quality and Usability of Toxicity Testing Studies
23
There are a number of factors to consider in evaluating whether an animal or human toxicity testing
study should be used in developing a toxicity value. The first is whether the study was conducted per
the appropriate testing guidelines for the regulatory agency. For EPA, these guidelines are the
harmonized test guidelines discussed in Section 3.1.5. Other guidelines include the Good Laboratory
Practice (GLP) and the Food and Drug Administration (FDA) and Organization for Economic Co-Operation
and Development (OECD) guidelines. Per these guidelines and other relevant documents (see for
example EPA 1994, 2002, 2005, and 2008), factors to consider in the critical evaluation of the quality
and usability of toxicity testing studies include:
• What is the route of administration of test material?
• What is the animal species tested?
• What is the dose duration (acute, sub-chronic, or chronic)?
• Is the apparent difference treatment-related?
• Is the effect dose-dependent?
• Is the effect biologically significant (as opposed to statistically significant)?
• Are the effects seen in multiple species, strains, or both sexes?
• Are the results relevant to humans?
• Were the study results interpreted properly?
Is supporting evidence such as physiologically based pharmacokinetic modeling, metabolism
studies, or structure activity relationship studies available?
Note that both the individual studies and the database of human and animal toxicity testing studies can
be ranked as having low, medium, or high confidence based on an evaluation of these factors (see
Section 5.3.3).
5.3.2.2 Defining Adverse and Critical Effects
Another critical element in the evaluation of a toxicity value is how adverse and critical effects are
defined. An adverse effect is defined by EPA as the biochemical change, functional impairment, or
pathological lesion that impairs performance and reduces the ability of an organism to respond to
additional challenge (http://www.epa.gov/iris/help_gloss.htm). The lowest dose level at which an
adverse effect occurs is defined as the critical effect level and is typically expressed as the LOAEL or
lowest observable effect level (LOEL). A dose level at which there are no statistically or biologically
significant increases in the frequency or severity of any effect between the exposed population and its
appropriate control is the NOAEL. The critical effect level can also be determined using a benchmark
dose approach or categorical regression. Thus, it is useful to consider the following in checking a study:
• Were the study results interpreted properly?
• Was the effect identified as adverse truly a biologically significant adverse effect?
• Is the adverse effect consistent with what is known about the chemical and the other studies in
the database?
24
It is also important that the critical effect level be adjusted to the dose metric of interest (for example,
parts per million [ppm] in food to milligrams per kilogram per day [mg/kg-day] for the oral route), for
duration of exposure (such as from periodic to daily or continuous exposure), and scaled from an animal
to a human equivalent body weight or concentration. Without these adjustments, it is not possible to
compare effect levels on an equivalent basis. A study that might appear to have the lowest point of
departure on first glance may not when the correct dosimetric adjustments are made. The critical effect
(NOAEL or LOAEL, point of departure if using a benchmark dose approach, and categorical regression) is
used as the starting point for calculating toxicity reference values for threshold toxicants.
5.3.2.3 Derivation of Noncancer and Cancer Toxicity Values
As mentioned in Section 2.2.3, the methodologies used to calculate toxicity values are typically specific
to the regulatory agency involved. Understanding their differences and similarities are also useful when
potential Tier 3 toxicity values and competing values are evaluated. EPA, for example, uses an RfD
approach to calculate toxicity values for threshold toxicants administered by the oral route of exposure.
An RfC is estimated for the inhalation route. This approach determines the critical effect level in the
principal study or studies and applies uncertainty factors to account for:
(1) Variation in susceptibility among the members of the human population (inter-individual or
intraspecies variability);
(2) Uncertainty in extrapolating animal data to humans (interspecies uncertainty);
(3) Uncertainty in extrapolating from data obtained in a study with less-than-lifetime exposure
(extrapolating from subchronic to chronic exposure);
(4) Uncertainty in extrapolating from a LOAEL rather than from a NOAEL; and
(5) Uncertainty associated with extrapolation when the database is incomplete.
The default for each of these uncertainty factors is a value of 10. The exact value (10, 3, or 1) of the
uncertainty factor selected may depend on the quality of the studies available, the extent of the
database, and scientific judgment. Some factors to consider when the default factor of 10 is replaced
with a lesser value are chemical-specific toxicokinetic or toxicodynamic data, the severity of the effect,
the slope of the dose-response curve, and the presence of developmental and reproductive studies. For
a more in-depth discussion, please see EPA’s report titled A Review of the Reference Dose and Reference
Concentration Process (EPA 2002). When a toxicity value is evaluated from the ATSDR database (or any
other state, federal, or international regulatory program), the application and interpretation of
uncertainty factors will differ from EPA’s approach. Understanding these differences is important
because the application of uncertainty factors may alter the final toxicity value by 1 to 5 orders of
magnitude.
Some regulatory agencies, such as Health Canada, may use a margin of exposure (MOE) approach.
Instead of reducing the critical effect level by a number of uncertainty factors, the MOE approach
compares site-specific exposures directly with the critical effect level. The resulting ratio is then
evaluated to determine if there is an adequate margin of safety.
25
For carcinogenic substances, qualitative descriptors are often provided on the likelihood of a chemical
agent to cause cancer in humans. EPA currently uses five recommended standard hazard descriptors:
“Carcinogenic to Humans,” “Likely to Be Carcinogenic to Humans,” “Suggestive Evidence of Carcinogenic
Potential,” “Inadequate Information to Assess Carcinogenic Potential,” and “Not Likely to Be
Carcinogenic to Humans” (EPA 2005). Different regulatory agencies and health organizations will use
different qualitative descriptors. For example, IARC classifies carcinogens as Group 1 (carcinogenic to
humans), Group 2A (probably carcinogenic to humans), Group 2B (possibly carcinogenic to humans),
Group 3 (not classifiable as to its carcinogenicity to humans) and Group 4 (probably not carcinogenic to
humans).
Some regulatory agencies and health organizations will quantify the dose-response assessment of
carcinogens, while some may simply regulate a toxicant if it is deemed to be a possible carcinogen. EPA
provides a quantitative estimate of the dose-response relationship by fitting the cancer bioassay data
within the range of observation and deriving a point of departure (the lowest data point adequately
supported by the data). If the mode of action data supports nonlinearity, an RfD or RfC is calculated
from the point of departure. If the mode of action data indicate the dose response curve is expected to
have a linear component below the point of departure, a linear extrapolation below the point of
departure is used. The slope of this line is the slope factor. Agencies may differ on their interpretation
of whether the dose response curve is linear or non-linear below the point of departure, resulting in
different calculations of a cancer toxicity values.
Other regulatory agencies and health organizations, particularly in Europe and Asia (World Health
Organization [WHO], International Programme on Chemical Safety [IPCS], and International Life Science
Institute Europe) support a MOE approach for assessing carcinogens, regardless of the mode of action.
The MOE approach compares the margin between a dose or an exposure causing cancer in animals or
humans (for example, the point of departure) with the estimated human exposure to that substance.
The resulting ratio is then evaluated to determine if there is an adequate margin of safety.
5.3.3 Tier 3 Toxicity Value Confidence
This white paper proposes that the confidence in a particular Tier 3 toxicity value could be ranked as
low, medium, or high as part of a critical review. Ranking the level of confidence could be useful for
determining the relative appropriateness of using Tier 3 toxicity value in various steps of the human
health risk assessment process, as well as assisting with the selection of a value when competing values
are available. A value that receives a “low” confidence ranking may be helpful during the initial
screening process (for example, when determining if an analyte is a chemical of concern and should be
carried forward into the baseline risk assessment process); however, a toxicity value with a “low”
confidence ranking may be not be suitable for use in the baseline risk assessment or development of
preliminary remediation goals because of limitations in this value. For CERCLA and RCRA processes that
undergo more critical examination, a toxicity value with a “medium” or “high” confidence ranking would
be more appropriate.
26
Below are some examples using the guiding principles mentioned above and discussed in Section 2.2 in
applying confidence rankings to toxicity values.
The first element is the quality and usability of the animal and human studies used to derive the toxicity
values. If only one animal species is tested for a subchronic period of exposure using only one dose level
by a route of administration not consistent with the exposure route being evaluated at a CERCLA or
RCRA site, the confidence in the toxicity value would likely be considered to be “low.” The value could
be used during the screening process, but would likely be inappropriate for a baseline risk assessment.
If the contamination levels at a CERCLA or RCRA site exceed screening levels based on a Tier 3 value with
low confidence, then the risk assessor has several choices. One choice would be to move to a
qualitative assessment of the contaminant during the baseline risk assessment. Another choice would
be to submit the contaminant to the STSC for a more thorough evaluation and a second opinion on the
usability of the database and toxicity value. A third option would be to retain the Tier 3 value in the
baseline risk assessment and be prepared to defend the scientific credibility of the value as part of the
uncertainty assessment.
The second element is how the adverse and critical effects are defined. If the adverse effect is
consistent with the definition provided in EPA’s IRIS database (http://www.epa.gov/iris/help_gloss.htm)
and is both biologically and statistically significant, then a ranking of “medium” or “high” may be
assigned.
The third element is an examination of the methodology used to derive the quantitative toxicity value
from the defined adverse effect. If the methodology is consistent with the cancer or noncancer
methodology described in EPA’s IRIS database (http://www.epa.gov/iris/) or adequately accounts for
uncertainty and variability within susceptible populations, then a confidence of “medium” or “high” can
be assigned. The overall ranking from these elements will be useful in determining where in the CERCLA
or RCRA process the toxicity value would be most appropriate to use.
5.4 Options for Tier 3 Toxicity Value Consultations
There are several possible options for the types of decision-making bodies that could provide Tier 3
toxicity value consultations. Some of the possible options, which are discussed in the following sections,
include forming or consulting an Action Development Process Workgroup; forming or consulting a
headquarters or regional workgroup, or having individual regions evaluate and select values. In
addition, the range of potential options is further expanded when considering the scope of consultation.
For example, the requestor could be responsible for performing the evaluation and the consultation
workgroup provides only a brief review and approval. Alternatively, the consultation workgroup could
be charged with conducting the full evaluation of the potential Tier 3 toxicity value. Section 4.1.1.2
provides some examples of how this has been done previously.
27
One factor that should be considered in making the decision is the potential impact of the Tier 3 toxicity
value under consideration and whether it should be considered influential scientific information.
Consistent with EPA’s Information Quality Guidelines
(http://www.epa.gov/QUALITY/informationguidelines/) and the Office Management and Budgets Peer
Review Bulletin (http://www.whitehouse.gov/sites/default/files/omb/memoranda/fy2005/m05-03.pdf),
influential scientific information is that which the agency reasonably can determine will have or does
have a clear and substantial impact on important public policies or private sector decisions. Influential
scientific information is expected to maximize quality, objectivity, utility, and integrity.
In addition to the visibility and priority of the chemical, there are several other key issues that will need
to be considered in establishing processes for developing Tier 3 toxicity values. These issues include, but
are not limited to, the overall coordination and process for requesting consultations, contract support,
and documentation. Additional discussion on these issues is provided in the following “options”
sections and in Section 5.5
5.4.1 Action Development Process Workgroup
The Action Development Process (ADP) is the Agency’s accepted method for producing high-quality
actions, such as regulations, policies, and risk assessments. It ensures that EPA uses the best available
information to support its actions and that scientific, economic, and policy issues are adequately
coordinated with the various stages of action development. More information is available on the Office
of Policy, Economics & Innovation’s (OPEI) Intranet site http://intranet.epa.gov/adplibrary. Tier 3
toxicity values that would be considered influential scientific information should generally be developed
through the ADP. Typically, this process would be initiated by OSWER. Briefly, the process begins with a
tiering by the Regulatory Steering Committee. There are three possible tiers related to the level of
senior level management involvement and the extent of cross-agency influence: Tier 1 actions are
signed by the Administrator and typically have broad cross-agency influence, Tier 2 actions are signed by
Assistant Administrators and typically have some cross-agency influence, and Tier 3 actions are typically
signed by Office Directors and generally have limited cross-agency influence. Development of Tier 3
toxicity values using the ADP would typically be considered a Tier 3 action. The ADP has a number of
prescribed steps that are required for all Tier 1 and Tier 2 actions; Tier 3 actions can be less formal, but
typically include Office of Management and Budget (OMB)-led interagency review.
5.4.2 Headquarters Consultation
Headquarters, including offices within OSWER and ORD, have advised regions in the past on the use of
Tier 3 toxicity values. Typically, regions have submitted requests to OSWER, which has responded with
its recommendations. These requests have included consultations on chromium (VI), PCE, PFOA, and
PFOS. Generally, these consultations were led by OSWER, but also included input from ORD. In
addition, consultations were often coordinated among various offices within OSWER, including the
28
science advisor, OSRTI, and OEM. The scope of these consultations also varied. Whereas much of the
toxicity value evaluation for chromium (VI) was performed by Region 2, most of the toxicity value
evaluation for PFOS and PFOAs was performed by OSWER and consulting programs.
This approach remains a viable method for evaluating and selecting Tier 3 toxicity values, especially for
high-priority chemicals where consistency and headquarters support are paramount. The headquarters
consultation could continue to be performed on an “informal” basis, or a more formalized consultation
process could be adopted in the future. Under the informal process, regions would continue to send
requests to any of the multiple risk assessment and toxicology program contacts in OSWER including,
but not limited, to OSRTI, OEM, or PARMS. Those offices would be responsible for establishing the
consultation workgroup. Under the formal consultation process, it is envisioned that all consultations
would be led and authored by a designated office within OSWER (such as OSRTI) and include a small
group of technical experts and representatives from various programs, regions, and laboratories (such as
ORD).
Regardless of whether an informal or formal approach is taken, several key factors will need to be
considered for headquarters consultations. First, headquarters may need to establish a point of contact
for consultations to coordinate reviews. In other words, headquarters may need to designate an
individual or group of individuals who could receive Tier 3 consultation requests. Likewise, to eliminate
redundancy (same requests from multiple regions) and improve the communication of toxicological
information, the regional risk assessors may need to establish a process for submitting requests. The
OSWER Human Health Regional Risk Assessors Forum (OH2R2AF) and OH2R2AF toxicity workgroup
could fulfill this role. Furthermore, depending on the scope of the consult and the resource and time
constraints, contract support may be necessary to assist headquarters with the collection, evaluation,
coordination, and documentation of information pertaining to the consult.
There are several benefits to using headquarters consultations. Because of its role in providing guidance
and policy to the regions, and centralized location within the organization, headquarters-based
consultations, which may be provided by a designated office in headquarters, are more likely to
maintain a consistent approach in the application of review criteria compared with other alternatives
that may rely on multiple entities to provide consults. Furthermore, as a result of its position of
authority, headquarters consultations also add “greater weight and credibility” to a Tier 3 value.
Headquarters consultations are also more likely to include involvement from other program offices at
the national level (e.g.,OPP), which may add greater credibility to and support for a particular Tier 3
toxicity value.
Despite the benefits associated with headquarters consultations, there are some potential challenges.
The biggest challenge pertains to the perception that headquarters is setting policy. There are specific
requirements for headquarters for the development of guidance and policy (such as interagency and
OMB review). Although consultations are not equivalent to agency guidance or policy, the perception
that headquarters is setting policy, especially among high-priority chemicals, could stall efforts.
Consultations could be delayed if the program office has to defend perceptions of setting policy to
29
management and others. Subject matter experts from other program offices may also be reluctant to
provide input if it appears they are setting policy for their particular program.
Another potential challenge with this alternative is that it may not be well suited to handle low-priority
chemicals. Headquarters will tend to have the greatest interest in chemicals that have significant affects
on risk management decisions or that are found in numerous regions. Thus, headquarters could exhaust
its resources and time in high-priority chemicals and have little time to complete consults on low-
priority chemicals. Consults would also have to compete with other headquarters projects and
priorities. Therefore, headquarters may have difficulties in getting adequate technical support from
subject matter experts for the consult.
5.4.3 Regional Workgroup
Another method for evaluating and selecting a Tier 3 toxicity value is through the use of a regional
workgroup. The regional workgroup could be established as a formal regional workgroup or as an ad
hoc work group consisting of subject matter experts with expertise relevant to the chemicals being
evaluated. These workgroups would be led by and generally consist of regional risk assessors and
toxicologists.12 Headquarters risk assessors and toxicologists could be involved, but serve more or less
as advisors. It is anticipated that the regional workgroup would primarily focus on low- to medium-
priority chemicals, but may provide guidance on the high-priority chemicals that would not be
considered influential scientific information.
There are two existing regional workgroups that could evaluate and select Tier 3 toxicity values. They
include the RSL workgroup and the newly formed OH2R2AF toxicity workgroup. Because these
workgroups’ primary roles are to maintain the RSL Table and to address overall toxicity value needs and
issues within the regions, a separate workgroup focused on Tier 3 toxicity values may be a viable
alternative. However, under this alternative, such a workgroup may require coordination and direction
from an overarching workgroup, such as the RSL workgroup and OH2R2AF toxicity workgroup (see
below).
The role of these workgroups could vary significantly. The regional workgroup’s role could be limited to
advising regions that have identified a potential Tier 3 toxicity value, which may include evaluating the
toxicity value and providing recommendations regarding the candidate value. In addition to providing
consultations, the regional workgroup’s role could be expanded to identifying, reviewing, and providing
recommendations on Tier 3 toxicity values independent of requests from regions. This latter role would
likely require formation of a formal workgroup.
12
Because regional risk assessors that submit potential Tier 3 toxicity values may have significant knowledge of the
chemical, they may remain involved in the evaluation and selection process as a regional workgroup member or
advisor.
30
Although the level of effort of these workgroups will depend on their scope and the amount of
toxicological information available for a given compound, contract support may be necessary. Under
the consultation role, contract support would likely be limited and vary according to the chemical. The
requestor of the consult may perform the bulk of the evaluation. However, contract support may be
necessary for a workgroup that is routinely involved in identifying, reviewing, and providing
recommendations on Tier 3 toxicity values independent of requests.
5.4.3.1 Formal Regional Workgroup
A formal regional workgroup, presumably under the auspices of the OH2R2AF, could play a dual role as
a consulting workgroup and workgroup that actively identifies, reviews, and makes recommendations
on Tier 3 toxicity values. This workgroup would generally be composed of and led by regional staff. Its
membership could be fixed or consist of a small group of permanent members whereby subject matter
experts fill temporary membership positions on a chemical-specific basis. Likely roles for this
workgroup, in addition to the those listed above, may include evaluating existing Tier 3 toxicity values
provided in the RSL table and periodically reviewing Tier 3 sources for new or updated toxicity values.
Additionally, this group could derive new toxicity values. However, the roles involving periodic review
of existing Tier 3 toxicity values in the RSL table and the derivation of toxicity values fall outside the
scope of this white paper.
There are several strengths and limitations of establishing a formal regional workgroup. It is envisioned
that a formal regional workgroup would select a core membership, structure it's organization (perhaps
by developing a charter), and schedule regular meetings. Such a group could be more easily tracked in
terms of agenda and progress, and a formal structure would make the workgroup easier to manage and
have clearer expectations. In addition, both the workgroup and its members would be more visible to
headquarters and the regions and provide greater credibility to the selection of a toxicity value. In
addition, it is likely that a formal workgroup would more likely maintain a consistent process (for
example, in application of review criteria) for evaluating and recommending new Tier 3 toxicity values.
However, if the workgroup is formalized and core membership is fixed, the workgroup may lack
expertise and/or fail to reach out to others with expertise in a particular chemical or toxicity value
development (Ibid). Lack of subject matter expertise would limit the scientific credibility and usability of
the toxicity value, which is the end product. Furthermore, the workload may not require regularly
scheduled meetings, potential resulting in loss of focus and interest among the workgroup members and
less than satisfactory work products.
5.4.3.2 Ad Hoc Regional Workgroups
Regional workgroups, under the direction of a coordinating committee (such as the OH2R2AF toxicity
workgroup), could also be formed on an as needed basis to provide consultation on the use of Tier 3
toxicity values. The coordinating committee would receive Tier 3 consultation requests and be charged
with staffing an ad hoc regional workgroup with regional risk assessors and toxicologists with subject
matter expertise relevant to the chemical in question. The group’s charge would also include
31
establishing a workgroup chair (a regional risk assessor or toxicologist) who would be responsible for
leading the consultation and documenting the consult (drafting the memorandum). ORD and
headquarters could also participate on these workgroups, especially if the regions are lacking subject
matter expertise. Given that this workgroup would be formed on an as-needed basis, it is not likely that
it will be evaluating and providing recommendations on existing Tier 3 toxicity values or periodically
reviewing Tier 3 sources for new or updated toxicity values. Those roles would likely be retained by
existing workgroups, such as the RSL table workgroup and the regional risk assessors.
Regardless of whether the coordinating responsibilities fall within a new or existing workgroup, the
coordinating committee will have to put itself into position to receive Tier 3 toxicity value consultation
requests and assign workgroups in a timely and efficient manner. Thus, the coordinating committee will
have to maintain visibility among the regional risk assessors so that it is known to whom requests should
be sent. The coordinating committee will also have to maintain a list of subject matter experts to staff
the workgroups. Maintaining this list would likely require the coordinating committee to reach out to
the regional toxicologists and risk assessors and possibly others in headquarters to determine whether
they can and would participate on the workgroup should their expertise be needed.
There are several strengths and benefits with the use of ad hoc regional workgroups. Unlike the formal
regional workgroup, which is limited to the expertise of its members, an ad hoc regional workgroup
could be staffed with members who already have expertise on a particular chemical or chemical group.
This approach to staffing could decrease the amount of time it takes to provide a consult and provide
greater credibility/weight to the consult. In addition, ad hoc regional workgroups may also better
champion the needs and priority for a Tier 3 toxicity value on a chemical that has a region-specific or
limited geographic distribution in the environment. Unlike a formal workgroup or headquarters consult,
an ad hoc workgroup could be composed of members who all have an interest in the chemical in
question and completing a consult. However, this composition also could bias the consult. An ad hoc
regional workgroup would also be focused on one particular task and less likely to be distracted from
competing priorities, thereby decreasing the amount of time for a consultation and potentially
improving the quality of the review. Furthermore, assuming the ad hoc workgroups are well-
coordinated, this option would likely maximize available resource by spreading the responsibilities
among many versus a few.
Along with the strengths and benefits of an ad hoc workgroup, this option has its limitations and
challenges. Several of these limitations and challenges could stem from the coordinating committee. As
indicated above, coordination is a critical component of this option. Thus, this option would lack
effectiveness if the coordinating committee is poorly organized and managed. In addition, the
formation and staffing of an ad hoc work group for each new chemical under consideration may be
cumbersome and time consuming for the coordinating committee. Because the ad hoc regional
workgroup will likely be coordinated by a regional workgroup, it may also suffer from lack of
membership or input from EPA in headquarters and ORD (such as OSWER risk assessor or NCEA
scientist). From a planning perspective, an ad hoc workgroup may make it difficult to staff workgroups
32
with subject matter experts from ORD or headquarters on an as-needed basis, let alone regional subject
matter experts.
Although this option allows for the tailoring of a workgroup around a particular expertise, multiple ad
hoc workgroups can pose some additional challenges. The use of the ad hoc approach could reduce the
likelihood that a consistent process would be maintained for evaluating and recommending new Tier 3
toxicity values. One workgroup may apply evaluation criteria differently than another group. Thus,
additional guidance and direction on the use of criteria may be needed to improve consistency.
Furthermore, an ad hoc workgroup needs a mandate or direction that will not ultimately put it at odds
with another Tier 3 workgroup (clarity of relationship between ad hoc workgroups and the RSL
Workgroup).
5.4.4 Joint Headquarters/Regional Workgroup
Risk assessors and toxicologists in the regions and headquarters (OSWER and ORD) have had a long
history in working together in developing and implementing risk assessment guidance and toxicological
assessments pertaining to Superfund and RCRA. In recent years, additional efforts (such as OH2R2AF)
have been undertaken to enhance communication between headquarters and regional Superfund and
RCRA risk assessors. A joint workgroup consisting of regional and headquarters risk assessors and
toxicologists could be established to provide consults on Tier 3 toxicity values because many of these
efforts involve workgroups consisting of a mixture of regional headquarters representatives. This option
is nearly identical to the regional workgroup option discussed in Section 5.4.3, except that this
workgroup could be led by either a headquarters or a regional risk assessor and would have to include
members from both regions and headquarters. Note that the regional workgroups do not necessarily
have to include headquarters representatives. Based on headquarters’ greater role in such a
workgroup, it is likely that this workgroup could work on medium- to high-priority chemicals.
The joint regional and headquarters workgroup also shares many of the same strengths and limitations
that the regional workgroup option may offer. In addition, this option allows for more coordination
between headquarters and the regions, which could provide greater transparency and credibility to Tier
3 toxicity value consultations over a regional workgroup. A greater role for headquarters may also
increase the likelihood that subject matter experts from headquarters will be involved in providing the
consult. However, the share of power between the regional risk assessors and headquarters could limit
the joint workgroup’s effectiveness. Competing interests (completing a site risk assessment versus
setting policy) could slow the workgroup activity.
5.4.5 Individual Regions
Under this approach, individual regions would continue to use their current methods for identifying and
selecting Tier 3 toxicity values. With the exception of the RSL table (and its predecessors), which have
provided recommendations on Tier 3 values, regions have already been largely responsible for
identifying Tier 3 toxicity values and providing guidance to responsible parties, states, and other entities.
33
However, regions have consulted headquarters and other regions for high-priority chemicals (such as
chromium VI) or chemicals commonly found at sites. Therefore, this approach is anticipated for use
with low- to medium-priority chemicals. The development of Tier 3 toxicity values for high-priority
chemicals will likely need the input from a regional workgroup or headquarters, especially risk-driving
chemicals. As stated in the 2003 OSWER toxicity value hierarchy, “Consultation with the STSC or
headquarters program office is recommended regarding the use of the Tier 3 values for Superfund
response decisions when the contaminant appears to be a risk driver for the site” (EPA 2003).
There are several strengths with the individual regions approach. To begin with, a relatively quick
turnaround time is associated with the approach. Rather than waiting for a response from headquarters
or a workgroup, decisions can be made within the region which assists in a quick turnaround time.
Following the individual regions approach allows regions to retain control of the selection of Tier 3
values. Furthermore, it allows for development of a more complete and thorough risk assessment,
which limits the possibility of underestimating risks.
As with the previous approaches, there are several limitations to individual regions evaluating and
selecting Tier 3 values. For instance, there is potential for lack of transparency and consistency with
regard to decision making. At times, information is not shared outside of the region, or even within the
region (between the programs). The lack of transparency (or information sharing) creates a problem
when different Tier 3 values are recommended by different regions. Because the criteria for selecting a
Tier 3 value do not specify the level of peer review, it is possible that several values could be chosen for
a chemical by different regions. The credibility of such a toxicity value is more likely to be questioned by
a responsible party (RP), resulting in a greater chance of challenge, especially for risk-driving chemicals,
which draw an additional level of scrutiny. Since the credibility of regionally selected Tier 3 values may
vary greatly, it is important to consult experts who can identify limitations of published values.
However, by definition, the regional approach discourages seeking expert advice across regions in
decision making. This lack of a cross-regional approach contributes to the limitations since the
toxicological expertise of the decision-maker within each region may vary extensively. Finally, this
approach does not address high-priority chemicals, which may need to be sent to headquarters for a
decision. It should also be noted that although it is possible for individual regions to identify available
Tier 3 toxicity values for certain chemicals of use and interest, regions often lack appropriate resources
and expertise to adequately evaluate and select a Tier 3 value. In such instances, assistance from
headquarters and other groups are often necessary.
5.5 Documentation
As noted in previous sections, transparency is a necessary component of a Tier 3 toxicity value.
Therefore, identification and selection of a Tier 3 toxicity value by EPA risk assessors must continue to
be transparent. Transparency includes documenting the decisions and recommendations regarding the
selection of a Tier 3 toxicity value and its supporting toxicological assessments and making these
documents available to the public. The following sections discuss potential methods for documenting
34
and distributing decision documents and alternatives (repositories) for warehousing decision documents
and supporting documentation (for example, toxicological assessments).
5.5.1 Decision Documents and Distribution
As shown in Section 4.2 and Appendix B, consults and recommendations on Tier 3 toxicity values have
taken the form of e-mails, formal memoranda, or listings in a table (the RSL table) and the level of detail
regarding the support of these values has differed. Although future consults and recommendations may
take several forms, development of a process for selecting a Tier 3 toxicity value may need to consider
the level of formality needed in consults and recommendations and the type of information to be
included in the consult or recommendation. For example, formal signed memoranda may offer more of
an authoritative voice than informal e-mails. With regards to the types of information to be provided in
consults or recommendations, it may include, but may not be limited to, the following:
Transparency, peer-review, and availability criteria met,
Summary of the underlying studies,
Methods for toxicity value derivation,
Uncertainty Factors (RfCs and RfDs),
Carcinogenic mechanism of action (MOA) (if available),
Target organ and critical effect, and
Confidence in toxicity value.
Also, before decision documents and toxicological assessments are warehoused (see Section 5.5.2),
timely notification of such decisions may be of interest to regional risk assessors. Regional risk assessors
have expressed interest in what other regions are doing to avoid re-inventing the wheel or being
inconsistent. However, notification does not necessarily mean that all regional decisions have to be
distributed outside of the region. There is the potential for inconsistency or that the value is not used in
a risk assessment because it may take some time between a decision on a Tier 3 toxicity value and its
use, for example, upload into a database. Thus, a process for selecting a Tier 3 toxicity value, should
consider a method for notifying regional risk assessors of any decisions regarding a Tier 3 toxicity value.
Typically, e-mails have been an effective tool for distributing this type of information and have been the
case with most headquarters consults. However, these e-mails have often been distributed from the
requesting region and may not have been distributed to all regional risk assessors. In addition, e-mails
may not always be read by all recipients. Other potential methods that could expand the risk assessor
audience may include broadcasts in the OH2R2AF newsletter or during the OH2R2AF calls. Finally, some
consideration should be given to how this information will be shared with other audiences (such as state
risk assessors before they are sent to a repository.
5.5.2 Repositories
35
Decision documents and supporting documentation (in this case, toxicological assessments) behind a
Tier 3 toxicity value must be stored and available for retrieval by risk assessors, risk managers, and the
public. The following sections discuss potential alternatives for warehousing this information. In
addition, the potential repositories discussed below may not apply to all situations because individual
regions may continue to develop their own Tier 3 values internally. However, it is expected that the
regions that develop their own values would be responsible for storing their decision documents and
supporting documentation, unless they plan to distribute the values beyond their region.
In addition, on-line repositories will require storage space, routine maintenance, and a point of contact
(for adding or revising a Tier 3 toxicity value). Although it is not the intent of this document to discuss
these issues in depth, costs and resources associated with storage and maintenance of decision
documents and supporting documentation will have to be considered and evaluated. Given these
potential constraints and other considerations (duplication of effort), links to non-EPA websites that
contain the toxicological assessments may be a viable alternative to storing the toxicological
assessments on EPA’s website.
5.5.2.1 PPRTV Assessments Electronic Library
The PPRTV Assessments Electronic Library is a potential repository for Tier 3 toxicity values. The PPRTV
electronic library, which has recently become publically available, is administered by OSRTI and
maintained by Oak Ridge National Laboratory under an interagency agreement. Notwithstanding
contractual arrangements, an additional menu could be added to the PPRTV electronic library to house
Tier 3 toxicity values. Similar to the PPRTVs, the menu could contain a list of all chemicals with Tier 3
toxicity values. When a given chemical is selected, the user would be sent to a page that contains the
Tier 3 toxicity values, decision documents, and the toxicological assessments.
5.5.2.2 Superfund Health Risk Technical Support Center (STSC)
The STSC provides technical support to EPA program and regional offices in the area of human health
risk assessment, such as the development of PPRTV assessments and scientific consultations. In years
past, the STSC has served as a repository for health risk assessment documents, such as hard copies of
HEAST derivation support documents. For these reasons, the STSC could serve as a repository for Tier 3
consults, recommendations, and supporting documentation. However, , STSC may not be a viable
alternative for storing recommendations on non-EPA toxicity values and their technical support
documents because the STSC develops PPRTVs and provides support for interpreting EPA publications
and guidance.
5.5.2.3 RSL Table Website
36
The RSL table website, which is posted by Regions 3, 6, and 9, is another potential repository for Tier 3
toxicity values. The RSL table website appears to be a logical choice as a potential repository for
supporting documentation because the RSL table is typically the first EPA document to post Tier 3
toxicity values. The user’s guide and supporting tables could be expanded to include a page that
contains the decision documents. This page could also provide the toxicological assessments or links to
the toxicological assessment on non-EPA websites. Because the RSL summary table already contains
fields for toxicity values, a separate location listing Tier 3 toxicity values would not be necessary.
Furthermore, although the RSL table is not an original source of toxicity values, it often serves as the
initial destination for Superfund and RCRA risk assessors seeking the most current toxicity values used
by EPA. Thus, use of the RSL table as a repository location for Tier 3 toxicity values could decrease the
number of locations risk assessors would have to search for toxicity values. However, as noted above,
the RSL table and its supporting documentation (such as the User’s Guide) are posted on the Region 3, 6,
and 9 websites. While only one Region (Region 3) stores the files (the other two provide links only), this
option would require approval and coordination with the Regions’ IT and risk assessment staff and
management. Note that it is unknown whether the regions currently storing the RSL tables are capable
of and willing to take on this additional duty as doing so requires additional storage and resources.
Furthermore, the layout of a Tier 3 toxicity value repository would be subject to the individual region’s
formatting preferences.
5.5.2.4 Tier 3 Toxicity Value Database
Although no such database exists at present, an on-line database strictly for Tier 3 values could be
developed. This database would be strictly for Tier 3 toxicity values and, like the IRIS and PPRTV
databases, its location will be readily identifiable as a source for recommended Tier 3 toxicity values. It
is envisioned that it would be formatted similar to the PPRTV library with drop-down menus. Although
such a site would provide a centralized and distinct location for Tier 3 toxicity values, it may require a
significant amount of additional money and resources to design and maintain compared with the use of
an existing on-line repository.
37
6 Recommended Option/Process and Path Forward
Overall, the Regional Tier 3 Toxicity Value Workgroup recommends a process that is flexible, consistent,
efficient, and results in the evaluation and selection of Tier 3 toxicity values that are scientifically
defensible. As discussed above, there is no “one size fits all,” especially with respect to the decision-
making body, for the evaluation and selection of Tier 3 toxicity values, and there are numerous
combinations of potential processes for identifying, evaluating, selecting, and documenting Tier 3
toxicity values. Therefore, the following recommendations are provided as a path a candidate Tier 3
toxicity value may take from its initial identification to final selection and documentation. Figure 2
below illustrates this proposed path. Note that the recommendations apply to future Tier 3 toxicity
values not already recommended by regional and headquarters risk assessors and the RSL table.
However, those involved in the implementation of all or certain aspects of this white paper should
consider existing Tier 3 toxicity values.
6.1 Toxicity Value Identification
The Tier 3 toxicity value workgroup recommends that the responsibility of identifying Tier 3 toxicity
values remains with the regional and headquarters risk assessors and existing regional risk assessor
workgroups (such as the RSL table team) to maintain flexibility and conserve time and resources. As
discussed previously, these groups are most likely to encounter a potential Tier 3 toxicity value during
development of a human health risk assessment and or a revision to the RSL table. Development of a
formal workgroup, as discussed in Section 5.4.3.1, will require time and resources. Furthermore, as
indicated in previous sections, the identification of potential Tier 3 values is not a frequent occurrence.
Thus, the value of a formal workgroup is unclear, especially when regional risk assessors and others will
likely continue to search for Tier 3 toxicity values in their routine work (risk assessments).
38
Figure 2. Proposed Tier 3 Toxicity Value Selection Process
Regions, HQ, or Workgroup
Toxicity value meets
Tier 3 criteria?
Consulting Body
Tier 3 Toxicity Value Criteria
High-Priority Tier 3 Toxicity Value Evaluated
Potential Tier 3 Toxicity Value is Identified, Evaluated Against 3 Basic Criteria, and Assigned Priority
Technical support
document(s)
Value not Recommended
Yes No
Potential Tier 3 Toxicity Value Meets 3 Basic
Criteria? No
Value not recommended
High- or Low-Priority?
Yes
Low-Priority Tier 3 Toxicity Value Evaluated
Toxicity value meets
Tier 3 criteria?
Region, RSL workgroup
Consulting Body Established By “Tier 3 Toxicity Value Steering Committee”
LowHigh
Value Recommended
Value not recommended
Yes No
Value Recommended
Notification and Decision Documents Uploaded to Tier 3
Toxicity Value Database
Decision Documents added to Regional Files
39
6.2 Initial Evaluation and Chemical Prioritization
Beyond a more thorough and complete evaluation of a potential Tier 3 toxicity value, some steps must
be taken to maintain a flexible and efficient process. We recommend that those who identify a
potential Tier 3 toxicity value ensure that the toxicity value meets the three basic criteria outlined in
Section 5.3.1, which include transparency, peer-reviewed, and public availability. Of course, these
criteria are general in scope and a potential Tier 3 value meeting all three criteria at some level does not
guarantee that it is scientifically defensible for use in human health risk assessments. At this time, other
factors may also be considered and used to eliminate a potential Tier 3 value (for example, extrapolation
of a toxicity value from an occupational standard, such as an Occupational Safety and Health
Administration permissible exposure limit).
During the initial evaluation, this white paper recommends that the chemical be designated a low or
high priority according to the prioritization criteria in Section 5.2. This designation is essential because it
provides the basis for the recommendations in Section 6.3 on the type of consulting body to become
involved. Note that additional prioritization of “high” priority chemicals will occur by the “Tier 3 Toxicity
Value Steering Committee” (see Section 6.3.2.1). Because two of the prioritization criteria include the
chemical’s prevalence across the regions and level of interest at the national level (whether it would
become the subject of a rule-making, for example), not to mention the potential subjective nature of
those determinations, this white paper recommends that these efforts be coordinated with risk
assessors and program representatives from other regions and headquarters via the “Tier 3 Toxicity
Value Steering Committee.”
6.3 Consulting Body
It is of the opinion of the Tier 3 toxicity value workgroup that no single process for evaluating and
selecting a Tier 3 toxicity value will be the most efficient and timely for all potential scenarios where a
potential Tier 3 toxicity value becomes available. Yet, the Tier 3 toxicity value workgroup also
recognizes that a more formal process needs to be established to promote greater consistency and
transparency among the regions. To meet these needs, this white paper recommends two separate
approaches for evaluating and selecting a Tier 3 toxicity value. Because a chemical’s significance and
priority have previously defined the level of involvement by regional and headquarters risk assessors
and toxicologists, it also serves as the critical determinant in selecting the appropriate approach.
Specific details on the two approaches are provided in the following sections.
6.3.1 Low-Priority Chemicals
This white paper recommends that the Tier 3 toxicity values be evaluated and selected by the individual
regions for chemicals that are designated as “low priority.” However, this alternative does not
necessarily preclude a region from consulting with others outside the region (such as STSC) regarding
the use of a particular Tier 3 toxicity value. The “individual region” option appears to be the most
practical for the “low-priority” chemicals, especially because it may allow for quicker decision making.
40
Chemicals with regional significance only, for example, may not draw enough interest from risk
assessors from other regions or headquarters to staff workgroups, which could stall efforts to evaluate
and select a value. A quick turnaround time is beneficial for non-risk driving chemicals so that it does
not hold up decisions on risk-driving chemicals. Concerns with transparency and credibility are likely
minimal for “low-priority” chemicals, especially non-risk driving chemicals. In addition, the RSL
workgroup (under this approach) would continue to be responsible for evaluating and selecting Tier 3
toxicity values for “low-priority” chemicals because the RSL workgroup handles a wide array of
chemicals ranging from “low priority” to “high priority.”
6.3.2 High-Priority Chemicals
Even among high-priority chemicals, there may be varying expectations on the type of consult to be
performed. Thus, it does not appear practical to recommend a specific consulting body. Instead, this
white paper recommends a flexible and adaptive approach whereby potential Tier 3 toxicity value
consultations be elevated to a “Tier 3 Toxicity Value Steering Committee.” This committee (see Section
6.3.2.1) will be responsible for establishing the consulting body (such as an ad hoc workgroup,
headquarters, or ADP) that best fits the situation and expectations of the risk assessors.
6.3.2.1 Tier 3 Toxicity Value Steering Committee
Although this white paper has not presented or evaluated potential workgroups that could fulfill the role
as the “Tier 3 Toxicity Value Steering Committee,” this white paper recommends that this role be
subsumed by the OH2R2AF toxicity workgroup. This role falls within the scope of the OH2R2AF toxicity
workgroup, which is to provide a forum to discuss and provide direction for OSWER human health risk
assessors with regard to the use of toxicity values in removal and remedial actions. Furthermore, the
OH2R2AF toxicity workgroup consists of members representing several regions and offices within
headquarters. This broad range of representation enables the workgroup to more easily reach out to
subject matter experts among the regions and headquarters, as well as to stay abreast of regional and
national risk assessment issues that may affect the level of review that a potential Tier 3 toxicity value
may receive.
Assuming the OH2R2AF toxicity workgroup takes on this responsibility, it may need to establish some
guidelines or processes for elevating these chemicals and selecting the appropriate decision-making
body. These guidelines and processes may include some of the following elements.
Points of contact for elevating the chemical to the OH2R2AF toxicity workgroup.
Criteria for determining which consulting entity will be used.
Listing of subject matter experts (including regional and headquarters scientists and program
representative) interested in participating in consultation workgroups.
Who will be responsible for performing the review and evaluating the potential Tier 3 toxicity
value’s health risk assessment (will it be performed by the requestor, consultant, ad hoc
workgroup members, or headquarters).
41
Information requirements (health risk assessments and other documents pertaining to the
derivation of a potential Tier 3 toxicity value).
Who will be responsible for submitting consultation requests (for example, regional risk
assessors, RTICs, managers, or division directors).
6.3.2.2 Other Considerations
This white paper generally recommends that the complete evaluation of potential high-priority Tier 3
toxicity values be the responsibility of the consulting body. This responsibility will ensure that subject
matter experts are critically reviewing the underlying data behind a toxicity value. However, there is the
potential that the consulting body may not perform the full review and evaluation. Previous examples
include consultations on chromium VI and PCE. Consulting bodies may have time and resource
constraints that prevent them (and individual members) from completing the full review and evaluation.
In addition, duplication of effort may be of concern if the requestors perform this activity after a
potential Tier 3 toxicity value has been initially identified as a matter of interest or routine. In these
instances, consulting bodies may require that others (the requestor) perform the full review and
evaluation of the toxicological support documentation and provide a summary of relevant information
to the consulting body for additional evaluation and decision-making. The scope of the consulting
body’s review and evaluation of the underlying toxicological information may vary. As a result, decisions
regarding the responsibility and extent of the review will likely require some degree of coordination with
the original consultation requestor. These activities could be facilitated by a “Tier 3 Toxicity Value
Steering Committee.”
6.4 Toxicity Value Evaluation
Regardless of who is responsible for evaluating a potential Tier 3 toxicity value, the same set of criteria
should be applied to all Tier 3 toxicity value evaluations. This white paper recommends that the ECOS
criteria, guiding principles, and other relevant criteria and guidance outlined in the white paper be
adopted as criteria for evaluating potential Tier 3 toxicity values. In addition to adopting the
aforementioned criteria, this white paper also recommends that the confidence in the toxicity value be
described in the evaluation. Evaluating and assigning confidence to toxicity values including the
underlying study and overall database are standard practice and potentially critical elements in risk
management decision-making. Confidence in a Tier 3 toxicity value would also be significant (a deciding
factor) in instances where there are competing Tier 3 values.
Also, per Section 5.3.2, it is critical that those involved in the evaluation and selection process have, at a
minimum, a basic understanding of how to evaluate and assess the data usability of toxicity studies, the
adverse and critical effect levels in a study, and the methodologies used to derive toxicity values.
Although these skills are likely to be present among the members of regional and headquarters
workgroups, it is less certain at the “individual region” level. Thus, training and educational
opportunities pertaining to the aforementioned skills should continue to be a priority among the risk
assessors.
42
6.5 Documentation
The following recommendations on documentation are generally intended to address high-priority
chemicals. In keeping with the theme of “low-priority” chemicals, decisions on how regions document
and store “low-priority” Tier 3 toxicity values will be left to the regions and RSL workgroup. However,
the Tier 3 toxicity value workgroup recommends that the regional risk assessors are notified of the
selection of Tier 3 toxicity values in case these chemicals ever come up in other regions. To make this
process efficient and less of a burden on the risk assessors who select a value, it is recommended that
notification and storage of decision documents be coordinated through the “Tier 3 toxicity value
steering committee.”
6.5.1 Decision Documents
This white paper recommends that a formal system be put into place that documents selection of a Tier
3 toxicity value. This white paper further recommends that all decision documents for high-priority
chemicals be provided in a formal memorandum from the selecting entity to the original requestor(s),
“Tier 3 toxicity value steering committee” and other relevant workgroups, such as the RSL workgroup
and the OH2R2AF toxicity workgroup (if different from the steering committee). The memorandum
should provide the rationale for selecting a value (how it meets the evaluation criteria) and contain the
following information (where applicable):
Summary of underlying studies,
Methods for toxicity value derivation,
Uncertainty factors (RfDs and RfCs),
Carcinogenic MOA and cancer classification (if available),
Target organ/critical effect, and
Confidence in toxicity value (critical for competing values).
The recommendation above also applies to situations where the consulting body does not recommend
the use of a value or selects one value over another in the case of competing values. When a value is
not selected, the response will focus on the particular criteria that are not met or other technical
reasons for not recommending a value. If the rationale for rejecting a value is not documented, there is
the potential that the same requests could be made in the future.
6.5.2 Repository
This white paper recommends that Tier 3 toxicity value decision documents and related documents
(such as health risk assessments) be housed electronically at one of the existing EPA toxicity value
websites or electronic libraries. To avoid duplication of effort, this white paper also recommends that
43
decision documents for toxicity values not selected by the consulting body be housed in the repository.
Notwithstanding contractual and resource arrangements with EPA websites that contain toxicity value
information, use of an existing EPA on-line location would not add to the number of EPA websites to
search for a toxicity value and would make use of existing infrastructure and resources. In addition, it is
recommended that the electronic library be publicly available and follow a format similar to the PPRTV
electronic library (with drop-down menus)
Those involved in posting Tier 3 toxicity value consults, such as the “Tier 3 toxicity value steering
committee,” will have to consider whether the health risk assessment in support of a particular toxicity
value needs to be posted on the website and if so, how this information will be housed. Health risk
assessments can be lengthy documents, and posting them on EPA websites may not be feasible.
However, health risk assessments in support of toxicity values are often provided electronically by the
authors, which are typically federal and state health agencies (as is the case with ATSDR toxicological
profiles). Therefore, links to websites containing those assessments may suffice.
7 Summary
While EPA has multiple policies, guidance, and guidelines to assist and/or direct risk assessors in the
development and selection of toxicity values, specific guidance on selecting tier 3 toxicity values for use
in Superfund and RCRA cleanup programs is limited. As a result, regional risk assessors have shared
concerns over transparency and consistency of selecting Tier 3 toxicity values. In response, the Tier 3
44
Toxicity Workgroup developed this white paper to explore and recommend processes for enhancing the
selection of Tier 3 toxicity values.
The process of selecting Tier 3 toxicity values consists of several steps including the identification,
prioritization, evaluation, selection, documentation, and communication of Tier 3 toxicity values.
Chapters 1 and 2 provide background on guidance and policies regional risk assessors follow to identify
toxicity values and examples of some of the most commonly used federal, state and international
sources of Tier 3 toxicity values and toxicity data. Chapter 2 also introduced the similarities and
differences in how toxicity values are developed within each of those sources and recommended that a
basic understanding on how to evaluate and assess the data usability of toxicity studies, identify the
adverse and critical effect levels in a study and evaluate the regulatory-specific methodologies used to
derive toxicity values is useful for comparing, selecting, and developing chemical-specific toxicity values.
A number of publications, both internal and external to EPA, are summarized in Chapter 3, which
provide guidance on how to evaluate the underlying basis of a toxicity value and provide a suggested
framework for identifying and selecting toxicity values. Chapter 4 summarizes current and past
practices of how regional risk assessors have identified, evaluated, and selected Tier 3 toxicity values.
Chapter 5 explores various options for identifying, evaluating, selecting, and documenting Tier 3 toxicity
values. The chapter discusses alternatives for who would be responsible for identifying potential Tier 3
toxicity values and proposes a set of criteria for assigning priority to a chemical because a chemical's
priority will likely dictate the entity that will provide a Tier 3 consultation. Chapter 5 also proposes a
process for evaluating and selecting Tier 3 toxicity values, which includes two steps consisting of a basic
evaluation and a critical review. The remainder and bulk of the chapter explores the options for Tier 3
toxicity value consultations and options for documenting and communicating the evaluation and
selection of Tier 3 toxicity values. The options for documenting and communicating the selection of
Tier 3 toxicity values include methods on how to document and distribute decision documents to
regional risk assessors and alternatives for warehousing decision documents. The options for the Tier 3
toxicity value consultation process are summarized in the table below.
After consideration of the strengths and limitations of each of the alternatives and previous and current
methods of selecting Tier 3 toxicity values, this white paper recommends a general process that retains
flexibility, but also enhances consistency and transparency. Rather than recommend a “one size fits all”
approach that could hinder efficiency and lengthen decision-making, this white paper recommends two
approaches, one addressing low priority chemicals and the other addressing high priority chemicals.
Proposed criteria for assigning priority are presented in Section 5.2.
For low priority chemicals, this white paper recommends that Tier 3 toxicity value decision-making be
retained within the regions. While responsibility for selecting Tier 3 toxicity values remains within the
regions, this white paper encourages regions to consult others outside of their own region, such as the
OH2R2AF, RSL workgroup, and STSC. Regions may lack information, resources, and technical expertise
to conduct chemical prioritizations and to evaluate and select Tier 3 toxicity values.
45
In regard to high priority chemicals, this white paper recommends the establishment of a “Tier 3 Toxicity
Value Committee” that will be responsible for the overall coordination of the Tier 3 toxicity value
selection process. The “Tier 3 Toxicity Value Committee,” a role that can be subsumed by the OH2R2AF
toxicity workgroup, would be mainly responsible for establishing the consulting body, i.e., the group
responsible for evaluating and selecting a Tier 3 toxicity value, that best fits the needs and expectations
of the risk assessors for the specific chemical. In addition, while decisions on how regions document and
store “low priority” Tier 3 toxicity values will be left to the regions and RSL workgroup, a more formal
and structured process for documenting, storing, and communicating “high priority” Tier 3 toxicity value
selections is recommended. Specifically, this white paper recommends that all decision documents be
provided in a formal memo from the reviewers to the requestor and would apply to situations where a
toxicity value is recommended, not recommended, or one value is recommended over another, i.e.,
competing toxicity values. Furthermore, this whitepaper recommends that decisions be communicated
to the regional risk assessors, via the “Tier 3 Toxicity Value Committee,” and that the decision
documents and other relevant information (e.g., health risk assessments) be stored within existing EPA
toxicity value websites or electronic libraries.
Although this white paper recommends two approaches, it is important to point out that they both
share some common recommendations including elements of the identification, prioritization, and
evaluation steps. These common recommendations include, but are not limited to, prioritization criteria
(discussed above) and the criteria and guiding principles used to evaluate candidate Tier 3 toxicity
values. Regardless of the vehicle used to perform the evaluations, the same set of criteria and principles
should be used to evaluate all potential Tier 3 toxicity values. Furthermore, to ensure consistent and
proper application of review criteria, training will continue to be a critical for those individuals that may
be involved in the evaluation and selection process.
46
Table 1. Options for Tier 3 Consultations
Option Factors for Consultation Strengths Limitations
Action Development Process (ADP) Workgroup
ADP is the Agency’s method for producing high quality actions such as regulations, policies, and risk assessments. Tier 3 toxicity values considered influential scientific information should be developed through ADP. Process typically initiated by Office of Solid Waste and Emergency Response (OSWER). Tiering process begun by Regulatory Steering Committee based on level of senior management involvement and extent of cross-agency influence:
Tier 1—actions signed by Administrator and have broad cross-agency influence
Tier 2 – actions signed by assistant Administrator and have some cross-agency influence
Tier 3 – actions signed by Office directors and have limited cross-agency influence
** **
Headquarters Consultation Regions submit requests to Headquarters. Typically, consultations are led by OSWER with input from the Office of Research and Development (ORD). Consultations are often coordinated among offices of OSWER including the Science Advisor, OSTRI, and OEM. Currently primarily performed on an “informal” basis. Could be formalized in future with consistent designated lead office within OSWER. Key factors include:
Headquarters establish contact to receive Tier 3 requests
Regional risk assessors establish a consistent process for submitting requests
Contract support may be necessary to assist within consultation
Promote consistency among regions
More likely to maintain consistent process for providing consultations
Add “greater weight and credibility to Tier 3 values
Perception that Headquarters is setting policy
Not well-suited to handle low-priority chemicals
Regional Workgroup Formal or ad hoc group of subject matter experts with expertise relevant to chemicals being evaluated. Led and generally consisting of regional risk assessors and toxicologists. Primary focus would be on low- to medium-priority chemicals. Two existing regional workgroups:
Regional screening level (RSL) workgroup
Regional human health risk assessment forum (OH2R2AF) toxicity workgroup
Formal workgroup
Easier establishment and tracking of expectations and results
Visible to headquarters and regions resulting in greater credibility of Tier 3 values
Maintenance of consistent process Ad hoc workgroup
Formed with selected experts as necessary
May better champion needs and priority for regional-specific Tier 3 values
If well coordinated, will maximize results by spreading duties to many, rather than few
Formal workgroup
Fixed membership may fail to reach out to individuals/groups with particular expertise
Workload may not require regular meetings, resulting in loss of focus and interests among members
Ad hoc workgroup
May lack effectiveness if not well-coordinated
Formation and staffing of multiple ad hoc workgroups may be cumbersome
May suffer from lack of headquarters input
Reduced likelihood of consistent process
Joint Headquarters/Regional Workgroup Joint workgroup consisting of regional and headquarters risk assessors and toxicologists Similar to regional workgroup except the group could be led by either headquarters or regional individual and have members from both groups.
Similar to regional workgroup, as well as
Allows more coordination between headquarters and regions resulting in greater transparency and credibility of Tier 3 values
More likely to include subject matter experts from headquarters (as compared to regional workgroup)
Similar to regional workgroup, as well as
Sharing of power between headquarters and regions could limit effectiveness
Competing interests could slow workgroup activity
Individual regions Individual regions would continue to use current methods for identifying and selecting Tier 3 values. Anticipated for use primarily with low- to medium-priority chemicals; high priority chemicals expected to include headquarters input.
Relatively quick turn-around
Allows regions to maintain control of Tier 3 values
Allows development of more complete and thorough risk assessment
Potential lack of transparency and reduced credibility of Tier 3 values
Lack of cross-regional approach limits access to and use of varied regional expertise
Approach does not address high priority chemicals which require headquarters input
Potential lack of regional resources and expertise in evaluating and selecting a Tier 3 value
**Unlike the other options, the ADP generally applies to specific circumstance as indicated in Section 5.4.1, i.e., Tier 3 toxicity values that are considered highly influential scientific information. Thus, the strengths and limitations of the ADP were not evaluated in this white paper.
47
References
Agency for Toxic Substances and Disease Registry (ATSDR). 1997. Toxicological Profile for Tetrachloroethylene. U.S. Department of Health & Human Services, Public Health Service, Agency for Toxic Substances and Disease Registry.
Environmental Council of the States (ECOS). 2007. Identification and Selection of Toxicity Values/Criteria
for CERCLA and Hazardous Waste Site Risk Assessments in the Absence of IRIS Values. ECOS-DoD
Sustainability Work Group, Washington, D.C.
(International Agency for Research on Cancer (IARC). 1995. IARC Monographs on the Evaluation of Carcinogenic Risk of Chemicals to Humans. Volume 63. International Agency for Research on Cancer, Lyon, France.
McCarroll, Nancy, N. Keshava, J. Chen, G. Akerman, A. Kligerman, and E. Rinde. 2010. An Evaluation of the Mode of Action Framework for Mutagenic Carcinogens Case Study II: Chromium (VI). Environ. Mol. Mutagen. 51:89–111.
National Toxicology Program (NTP). 2008. NTP technical report on the toxicology and carcinogenesis
studies of sodium dichromate dihydrate (CAS No. 7789-12-0) in F344/N rats and B6C3F1 mice (drinking
water studies). Washington, DC: National Toxicology Program; NTP TR 546. Available online at
http://ntp.niehs.nih.gov/files/546_web_FINAL.pdf (accessed April 15, 2010).
New Jersey Department of Environmental Protection (NJDEP). 2009. Derivation of Ingestion-Based Soil
Remediation Criterion for Cr +6
Based on the NTP Chronic Bioassay Data for Sodium Dichromate
Dihydrate. Available on-line at: http://www.state.nj.us/dep/dsr/chromium/soil-cleanup-derivation.pdf
(accessed April 15, 2010)
New York State Department of Health (NYDOH). 2006. Trichloroethene Air Criteria Document. Center
for Environmental Health, Bureau of Toxic Substance Assessment, Troy, NY. Available on-line at
http://www.health.state.ny.us/environmental/chemicals/trichloroethene/docs/cd_tce.pdf.
U.S. Environmental Protection Agency (EPA). 1989. Risk Assessment Guidance for Superfund: Volume 1 -
Human Health Evaluation Manual (Part A). EPA/540/1-89/002. Office of Emergency and Remedial
Response, Washington, D.C.
EPA. 1991. Risk Assessment Guidance for Superfund: Volume 1 – Human Health Evaluation Manual (Part
B, Development of Risk-based Preliminary Remediation Goals ). EPA/540/R-92/003. Office of Emergency
and Remedial Response, Washington, D.C.
EPA, 1994. Methods of Derivation of Inhalation Reference Concentrations and Application
of Inhalation Dosimetry. Office of Research and Development, Research Triangle Park, NC.
EPA/600/8-90/066F. http://cfpub.epa.gov/ncea/cfm/recordisplay.cfm?deid=71993.
48
EPA. 1998. Toxicological Review of Hexavalent Chromium. U.S. Environmental Protection Agency,
Washington, D.C.
EPA. 2002. A Review of the Reference Dose and Reference Concentration Process. EPA/630/P-02/002F.
Risk Assessment Forum, Washington, D.C. Available on-line at
http://www.epa.gov/raf/publications/review-reference-dose.htm.
EPA. 2003. Human Health Toxicity Values in Superfund Risk Assessments. OSWER Directive 9285.7-53.
Office of Solid Waste and Emergency Response, Washington, D.C.
EPA. 2004. Risk Assessment Guidance for Superfund: Volume I – Human Health Evaluation Manual
(Part E, Supplemental Guidance for Dermal Risk Assessment). EPA/540/R/99/005. Office of Superfund
Remediation and Technology Innovation, Washington, D.C.
EPA. 2005. Guidelines for Carcinogen Risk Assessment. EPA/630/P-03/001F. Risk Assessment Forum.
Washington, D.C.
EPA. 2006a. Peer Review Handbook, 3rd Edition. EPA/100/B-06/002. Science Policy Council,
Washington, D.C.
EPA. 2006b. Peer Review Policy. From Stephen L. Johnson, Administrator, U.S. EPA, Washington D.C.
EPA. 2008. Scientific and Ethical Approaches for Observational Exposure Studies. EPA 600/R-08/062.
Office of Research and Development. Washington, D.C.
EPA. 2009. Risk Assessment Guidance for Superfund: Volume I – Human Health Evaluation Manual
(Part F, Supplemental Guidance for Inhalation Risk Assessment). EPA/540/R/070/002. Office of
Superfund Remediation and Technology Innovation, Washington, D.C.
A-1
Appendix A – OSWER and ORD Organizational Charts
A-2
Figure A-1. Office of Solid Waste and Emergency Response
Center for Program Analysis
Innovation Partnership &
Communication Office
Federal Facilities Restoration & Reuse
Office
Acquisition & Resources
Management Staff
Policy Analysis & Regulatory
Management Staff
Information Management &
Data Quality Staff
Office of Underground Storage Tanks
Office of Emergency
Management
Office of Resource
Conservation & Recovery
Office of Brownfields &
Land Revitalization
Office of Superfund
Remediation & Technology Innovation
Office of Program Management
Organization Management &
Integrity Staff
Office of the Assistant
Administrator
A-3
Figure A-2. Office of Research and Development
Office of Science Information
Management
Deputy Assistant Administrator
Chief of Staff
Science Policy
Deputy Assistant Administrator for
Science
Resources Management and
Administration
National Risk Management
Research Laboratory
National Homeland Security
Research Center
National Center for
Computational Toxicology
National Center for
Environmental Research
National Center for
Environmental Assessment
Office of the Science Advisor
EPA Science Advisor
Office of the Assistant
Administrator
National Program
Managers
Office of Administration
& Research Support
National Exposure Research
Laboratory
National Health and
Environmental Effects
Research Laboratory
B-1
Appendix B – Consultations
B-2
B-3
B-4
B-5
B-6
B-7
B-8
B-9
B-10
B-11
B-12
B-13
UNITED STATES ENVIRONMENTAL PROTECTION AGENCY WASHINGTON, D.C. 20460
OFFICE OF SOLI D w;.STE ;$0 EHERGENCY
RESPONSE June 12 o 2003
OSWERNo. 9285.7-75
MarciaL. Bailey, D. Env. Environmental Toxicologist U.S. Environmental Protection Agency, Region 10 Office of Environmental Assessment, Risk Evaluation Unit 1200 Sixth Avenue, OEA-095 Seattle, Washington 981 0 1
Dear Dr. Bailey:
I am responding to recent inquiries concerning cancer toxicity values to evaluate inhalation and ingestion risks from exposure to tetrachloroethylene, also commonly known as perchloroethylene or "PCE," and specifically whether it would be appropriate to use a California EnYironmental Protection Agency (Cal EPA) inhalation unit risk value and oral slope factor. This letter supercedes an earlier version of this letter, which identified an incorrect source of the oral slope factor. This letter is consistent with the earlier letter regarding the inhalation unit risk value and its source.
In the absence of relevant values in the U.S. Environmental Protection Agency (EPA) Integrated Risk Information System (IRIS) or a value from EPA's National Center for Environmental Assessment/Superfund Technical Health Risk Support Center (STSC), which are the first two tiers of human health toxicity values in the EPA Superfund hierarchy, we would support consideration of the Cal EPA inhalation unit risk value from th.e Air Toxics Hot Spots Program and the oral slope factor from the Cal EPA Public Health Goal in Drinking Water.
In general, Cal EPA develops its toxicity values in a manner which is quite similar to the EPA IRIS program, in that many of the same databases and considerations are used. Cal EPA's assessments used information from some of the same sources or studies that EPA typically considers in the IRIS program, including the most recent relevant studies known to exist, and also considered this information in a manner similar to the EPA IRIS program.
B-14
I
In summary, having consulted on this matter with the STSC, the Office of Emergency and Remedial Response (OERR) supports use of the Cal EPA Air Toxics Hot Spots Program
inhalation unit risk of 5.9 E-6 (pg!m3t 1 for Superfund sites as the best value available at this time until a U.S. EPA value becomes available. Having consulted with the STSC about the Cal
EPA Public Health Goal in Drinking Water oral slope factor of5.4E-1 (mglkg-day)"l for PCE, we also support the use of this value until a U.S. EPA value becomes available.
B-15
The Cal EPA presents a full, complete and transparent presentation of the relevant information on their development of these values on their internet website. Documentation on the Air Taxies Hot Spots Program inhalation unit risk \'alue can be found at this internet website: http://W\\w.oehha.ca.gov/air/hot soots/pdf/TSDNov2002.pdf . Since this website does not take you directly to the PCE discussion, and this can be difficult to find on the internet website, we have downloaded the eight pages pertaining to PCE and include them as an enclosure to this letter. Documentation on the Public Health Goal in Drinking Water oral slope factor can be found at this Cal EPA internet website: http://www.ot:hhaca.gov/water/phg/pdf/PCEAug200l.pdf Because of the size of this document (75 pages) and because this website does take you directly to this document, we haye not included this document as an enclosure to this letter. With respect to the transparency of any Superfund Program decisions which may use these values in selecting a response action, we recommend that the appropriate documentation from the Cal EPA website be provided, or the link to the relevant Cal EPA internet website be identified.
Thank you for your inquiry. If you have any questions, please contact Mr. Dave Crawford of my staff at (703) 603-8891 .
Sincerely,
Is!
Elizabeth Southerland, Deputy Director Office of Emergency and Remedial Response
cc: Harlal Choudhury ORD/NCEA/STSC Sarah Levinson, Region 1 Matthew Hale, OSWER/OSW Barnes Johnson, OSWER/OSW Renee Wynn, OSWER/FFRO James Woolford, OSWER/FFRO Regional Risk Leads, Regions l-1 0 Nancy Riveland, Superfund Lead Region Coordinator, USEPA Region 9 Paul Sieminski, RCRA Lead Region Coordinator, USEP A Region 6 OERR NARPM Co-Chairs Joanna Gibson, OERR Document Coordinator
Enclosure: California Environmental Protection Agency, Office of Environmental Health Hazard Assessment, Air Taxies Hot Soots Program Risk Assessment Guidelines. Part II, Technical Support Document for Describing Available Cancer Potency Factors, December 2002 (excerpt pertaining to tetrachloroethylene)
B-16
B-17
B-18
B-19
B-20
F344/N rats, and "clear evidence of carcinogenicity" of PCB fur both sexes of B6C3F 1 mice. IARC reevaluated the evidence of carcinogenicity of PCB in 1987 using data from the N1P study and concluded that there was sufficient evidence that PCB is carcin()genic ro animals (IARC, 1987). Other studies on PCB included those by Rampy et al. (1978) and Theiss et al. (1977). Rampy eta!. (1978) exposed male and female Sprague-Dawley rats to PCB by inhalation (300 or 600 ppm) 6 hours/day, 5 days/week for 12 months. Animals were subsequently ()bserved for 18 months. Pathological changes in the liver or kidney were not observed. Theiss and coworkers studied the ability ofPCE to induce lung adenomas in A/St male mice (Theiss et al., 1977). Animals 6 to 8 weeks old were given 80, 200, or 400 mg/kg ofPCE in tricapzylin (intraperitoneally) three times a week. Each group received 14, 24, or 48 injections. Treated animals did not exlnbit a significant increase in the average number of lung tumors when compared ro controls.
N. DERIVATION OF CANCER POTENCY
Basis tor Cancer Potency
Perchloroethylene has been observed to induce mononuclear cell leukemia in male and female rats and liver tumors in male and female mice (NTP, 1986). CDHS (1992) decided that the tumor incidence data from this study were suitable for use in developing a quantitative risk assessment
Methodology
Results from the 1986 N1P inhalation study were used as the basis for estimating the carcinogenic mk of PCB to humans. In this bioassay, PCE was 99.9"/o pure, and animals were exposed 6 hours/day, 5 dayslweek for 103 weeks. The mice in the 100 and 200 ppm dose groups were exposed .ro a timeweighted-average (TWA) of 16 and 32 ppm, respectively (e.g., I 00 ppm x 6 hours/24 hours x 5 days/7 days). Similarly, rats in the 200 and 400 ppm dose groups were exposed to a TWA of 33 and 66 ppm, respectively.
The CDHS staff used the metabolized dose, adjusted to continuous lifetime exposure, to calculate the carcinogenic p:ltency ofPCE (CDHS, 1992). There are several uncertainties using this approach; 1) It was assumed that oxidative metabolism leads to the production of carcinogenic metabolites but the ultimate carcinogen(s) has not bc:m well characterized. The metabolism ofPCE is not well quantified in humans, and 20-40"/o of the absorbed PCE has not been accounted for. 2) The pharrnacokinetic models used do not account for individual differences in metabolism and storage. The body burden depended on factors such as age, sex, exercise or workload, body mass, adipose tissue mass, pulmonary dysfunctional states, and individual differences in the intrinsic capacity to metabolize PCB.
Two phannacokinetic models, the steady-state and the PB-PK approaches were used. They incoipOrated an 18.5% estimated applied dose as the fraction of the dose that is metabolized in hmnans. For the low-dose PCB risk assessment, the Crump multistage polynomial (Crump, 1984) was chosen.
483
B-21
B-22
B-23
B-24
B-25
B-26